Processes and intermediates for producing azaindoles

ABSTRACT

The present invention relates to processes and intermediates for the preparation of compounds useful as inhibitors of Janus kinases (JAK).

CROSS REFERENCE TO RELATED APPLICATION

The present U.S. patent application claims the benefit of U.S.Application Ser. No. 61/504,351, filed on Jul. 5, 2011, and U.S.Application Ser. No. 61/636,296, filed on Apr. 20, 2012. Each of theseapplications is hereby incorporated by reference in its entirety.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to processes and intermediates for thepreparation of compounds useful as inhibitors of Janus kinases (JAK).

BACKGROUND OF THE INVENTION

The Janus kinases (JAK) are a family of tyrosine kinases consisting ofJAK1, JAK2, JAK3 and TYK2. The JAKs play a critical role in cytokinesignaling. The down-stream substrates of the JAK family of kinasesinclude the signal transducer and activator of transcription (STAT)proteins. JAK/STAT signaling has been implicated in the mediation ofmany abnormal immune responses such as allergies, asthma, autoimmunediseases such as transplant rejection, rheumatoid arthritis, amyotrophiclateral sclerosis and multiple sclerosis as well as in solid andhematologic malignancies such as leukemias and lymphomas. JAK2 has alsobeen implicated in myeloproliferative disorders, which includepolycythemia vera, essential thrombocythemia, chronic idiopathicmyelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloidleukemia, chronic myelomonocytic leukemia, chronic eosinophilicleukemia, hypereosinophilic syndrome and systematic mast cell disease.

Compounds described as kinase inhibitors, particularly the JAK familykinases, are disclosed in WO 2005/095400 and WO 2007/084557 the entirecontents of each of which are incorporated herein by reference. Alsodisclosed in these publications are processes and intermediates for thepreparation of these compounds. There remains however, a need foreconomical processes for the preparation of these compounds.

SUMMARY OF THE INVENTION

The present invention relates to processes and intermediates that areuseful for generating JAK inhibitors.

The present invention provides a process for preparing a compound ofFormula I:

or a pharmaceutically acceptable salt thereof, wherein R¹ is —H, —Cl or—F; R² is —H or —F; R³ is —C₁₋₄ aliphatic optionally substituted with1-5 occurrences of R⁵; R⁴ is —C₁₋₂alkyl optionally substituted with 1-3occurrences of R⁵; or R³ and R⁴ are taken together to form a 3-7membered carbocyclic or heterocyclic saturated ring optionallysubstituted with 1-5 occurrences of R⁵; each R⁵ is independentlyselected from halogen, —OCH₃, —OH, —NO₂, —NH₂, —SH, —SCH₃, —NHCH₃, —CN,or unsubstituted —C₁₋₂ aliphatic, or two R⁵ groups, together with thecarbon to which they are attached, form a cyclopropyl ring; R⁶ is —H orunsubstituted —C₁₋₂ alkyl; and R⁷ is a —CH₂CR₃ or —(CH₂)₂CR₃ whereineach R is independently —H or —F; comprising the step of: i) reacting acompound of Formula 1 with a hydrochloride salt of a compound Formula 2

in the presence of water, an organic solvent, a base, and a transitionmetal catalyst to generate a compound of Formula I.

In some embodiments, the organic solvent of step i) is an aproticsolvent. For example, the aprotic solvent of step i) is acetonitrile,toluene, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, methyltert-butyl ether, or any combination thereof.

In some embodiments, the organic solvent of step i) is a protic solvent.For example, the protic solvent of step i) is an alcohol selected frommethanol, propanol, isopropanol, butanol, tert-butanol, or anycombination thereof.

In some embodiments, the base of step i) is an inorganic base. Forexample, the inorganic base of step i) comprises tripotassium phosphate,dipotassium hydrogen phosphate, dipotassium carbonate, disodiumcarbonate, trisodium phosphate, disodium hydrogen phosphate, or anycombination thereof. In other examples, the inorganic base of step i)comprises an alkali metal hydroxide such as NaOH, KOH, or anycombination thereof.

In some embodiments, the transition metal catalyst of step i) is apalladium catalyst. For example, the palladium catalyst of step i)comprises palladium(II)acetate,tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0), or any combination thereof. Inother implementations, the palladium catalyst is generated in situ, andthe reaction of step i) occurs in the presence of a phosphine ligand(e.g., triphenylphosphine). And in other examples, the palladiumcatalyst of step i) comprises

or any combination thereof.

In some embodiments, the reaction of step i) is performed at atemperature between about 50° C. and about 110° C. (e.g., between about60° C. and about 95° C. or between about 70° C. and about 80° C.)

In some embodiments, the reaction of step i) is performed withagitation. For example, the reaction is performed in a vessel containinga stir bar or mixer that agitates the reaction mixture.

In some embodiments, the reaction of step i) occurs in about 17 hours.

In some embodiments, the reaction of step i) is about 86% complete inabout 5 hours.

In some embodiments, the reaction of step i) is about 99% complete inabout 17 hours.

Other embodiments further comprise the steps of: ii) deprotecting acompound of Formula 3 to generate a compound of Formula 4:

and; iii) reacting the compound of Formula 4 with HNR⁶R⁷ in the presenceof a coupling agent and an organic solvent to generate the compound ofFormula I.

In some embodiments, step ii) comprises deprotecting the compound ofFormula 3 in the presence of a base. For example, the base of step ii)comprises an inorganic base. In some examples, the inorganic base ofstep ii) is an alkali metal hydroxide such as NaOH, KOH, or anycombination thereof.

In some embodiments, HNR⁶R⁷ is 2,2,2-trifluoroethylamine.

In some embodiments, the reaction of step iii) is performed in thepresence of an organic base. In some examples, the organic base of stepiii) comprises a tertiary amine. For example, the tertiary amine of stepiii) comprises N,N-diisopropylethylamine, triethylamine, or anycombination thereof.

In some embodiments, the coupling agent of step iii) comprisespropylphosphonic anhydride.

In some embodiments, the organic solvent of step iii) comprises ahalogenated hydrocarbon, an alkyl substituted tetrahydrofuran, or anycombination thereof. For example, the organic solvent of step iii)comprises an alkyl substituted tetrahydrofuran such as2-methyltetrahydrofuran. In other examples, the organic solvent of stepiii) comprises a halogenated hydrocarbon such as dichloromethane ordichloroethane.

Some embodiments further comprise the steps of: iva) reacting a compoundof Formula 5 with bromine in an organic solvent to generate a compoundof Formula 6:

va) reacting the compound of Formula 6 with p-toluenesulfonyl chlorideto generate a compound of Formula 7:

vi) reacting the compound of Formula 7 with triisopropyl borate, in thepresence of an organic solvent and a strong lithium base to generate acompound of Formula 8:

andvii) esterifying the compound of Formula 8 with pinacolate alcohol in anorganic solvent to generate a compound of Formula 1.

Some embodiments further comprise the steps of: ivb) reacting a compoundof Formula 5 with p-toluenesulfonyl chloride to generate a compound ofFormula 9:

vb) reacting the compound of Formula 9 with N-bromosuccinimide togenerate a compound of Formula 7:

vi) reacting the compound of Formula 7 with triisopropyl borate, in thepresence of an organic solvent and a strong lithium base to generate acompound of Formula 8:

vii) esterifying the compound of Formula 8 with pinacolate alcohol in anorganic solvent to generate a compound of Formula 1.

Some embodiments further comprise the step of: viiia) reacting acompound of Formula 10, wherein R⁸ is a —C₁₋₄alkyl, with a compound ofFormula 11:

in the presence of an organic base and an organic solvent to generate amixture comprising a compound of Formula 12 and a compound of Formula13:

Some embodiments further comprise the steps of: ixa) deprotecting thecompound of Formula 12 and the compound of Formula 13 in the presence ofan inorganic acid to generate a mixture comprising a compound of Formula2 and a compound of Formula 14:

xa) reacting the mixture comprising the compound of Formula 2 and thecompound of Formula 14 with HCl in the presence of an organic solvent togenerate the hydrochloride salts of the compound of Formula 2 and thecompound of Formula 14; andxia) recrystallizing the mixture of the hydrochloride salts of thecompound of Formula 2 and the compound of Formula 14 to generate thehydrochloride salt of the compound of Formula 2.

Some alternative embodiments further comprising the steps of: viiib)reacting a compound of Formula 11 with an acid salt of a compound ofFormula 15 in the presence of a solvent and a base to generate thecompound Formula 2:

andixb) reacting the compound of Formula 2 with HCl to generate thehydrochloride salt of the compound of Formula 2.

In some embodiments, the base of step viiib) is an inorganic baseselected from tripotassium phosphate, dipotassium hydrogen phosphate,dipotassium carbonate, disodium carbonate, trisodium phosphate, disodiumhydrogen phosphate, or any combination thereof.

In some embodiments, the solvent of step viiib) comprises water.

In some embodiments, the solvent of step viiib) further comprises analcohol selected from methanol, ethanol, propanol, iso-propanol,butanol, tert-butanol, or any combination thereof.

In some embodiments, the reaction of step viiib) is performed at atemperature of from about 70° C. to about 120° C. (e.g., 80° C. to about100° C.).

The present invention also provides a process for preparing a compoundof Formula 4:

wherein R¹ is —H, —Cl or —F; R² is —H or —F; R³ is —C₁₋₄ aliphaticoptionally substituted with 1-5 occurrences of R⁵; R⁴ is —C₁₋₂alkyloptionally substituted with 1-3 occurrences of R⁵; or R³ and R⁴ aretaken together to form a 3-7 membered carbocyclic or heterocyclicsaturated ring optionally substituted with 1-5 occurrences of R⁵; eachR⁵ is independently selected from halogen, —OCH₃, —OH, —NO₂, —NH₂, —SH,—SCH₃, —NHCH₃, —CN, or unsubstituted —C₁₋₂ aliphatic, or two R⁵ groups,together with the carbon to which they are attached, form a cyclopropylring; comprising the step of: ia) reacting a compound of Formula 1 witha hydrochloride salt of a compound Formula 2,

in the presence of water, an organic solvent, a base, and a palladium(Pd) catalyst selected from

or any combination thereof, to generate a compound of Formula 3, and

ii) deprotecting the compound of Formula 3 to generate the compound ofFormula 4.

In some embodiments, the organic solvent of step ia) is an alcohol. Forexample, the alcohol of step ia) is selected from methanol, ethanol,propanol, isopropanol, butanol, tert-butanol, or any combinationthereof.

In some embodiments, the base of step ia) is an inorganic base. Forexample, the inorganic base of step ia) is an alkali metal hydroxidesuch as NaOH, KOH, or any combination thereof.

In some embodiments, the reaction of step ia) is performed at atemperature between about 50° C. and about 110° C. (e.g., between about60° C. and about 95° C. or between about 70° C. and about 80° C.).

In some embodiments, step ia) is performed with agitation. For example,the reaction is performed in a vessel containing a stir bar thatagitates the reaction mixture.

In some embodiments, the reaction of step ia) occurs in about 17 hours.

In some embodiments, the reaction of step ia) is about 86% complete inabout 5 hours.

In some embodiments, the reaction of step ia) is about 99% complete inabout 17 hours.

In some embodiments, the deprotection of step ii) is performed in thepresence of a base. In some examples, the base of step ii) is aninorganic base. In other examples, the inorganic base of step ii) is analkali metal hydroxide such as KOH, NaOH, or any combination thereof.

Some embodiments further comprise the steps: viiib) reacting a compoundof Formula 11 with an acid salt of a compound of Formula 15 in thepresence of a solvent and a base to generate the compound Formula 2

andixb) reacting the compound of Formula 2 with HCl to generate thehydrochloride salt of the compound of Formula 2.

In some embodiments, the base of step viiib) is an inorganic baseselected from tripotassium phosphate, dipotassium hydrogen phosphate,dipotassium carbonate, disodium carbonate, trisodium phosphate, disodiumhydrogen phosphate, or any combination thereof.

In some embodiments, the solvent of step viiib) comprises water.

In some embodiments, the solvent of step viiib) further comprises analcohol selected from methanol, ethanol, propanol, iso-propanol,butanol, tert-butanol, or any combination thereof.

In some embodiments, the reaction of step viiib) is performed at atemperature of from about 70° C. to about 120° C. (e.g., from about 80°C. to about 100° C.).

The present invention also provides a process for preparing a compoundof Formula 1:

or a pharmaceutically acceptable salt thereof, wherein R¹ is —H, —Cl, or—F; comprising the steps of: iva) reacting a compound of Formula 5 withbromine in an organic solvent to generate a compound of Formula 6:

va) reacting the compound of Formula 6 with p-toluenesulfonyl chlorideto generate a compound of Formula 7:

vi) reacting the compound of Formula 7 with triisopropyl borate, in thepresence of an organic solvent and a strong lithium base to generate acompound of Formula 8:

andvii) esterifying the compound of Formula 8 with pinacolate alcohol in anorganic solvent to generate a compound of Formula 1.

In some embodiments, the organic solvent of step iva) is an aproticsolvent. For example, the aprotic solvent of step iva) isdimethylformamide.

In some embodiments, the reaction of step iva) is performed at atemperature of about −5° C. to about 30° C. (e.g., about 0° C. to about10° C.).

In some embodiments, the reaction of step va) is performed in thepresence of sodium hydride.

In some embodiments, the reaction of step va) is performed at atemperature of about 0° C. to about 30° C. (e.g., about 5° C. to about25° C. or about 10° C. to about 20° C.).

In some embodiments, the strong lithium base of step vi) is n-butyllithium.

In some embodiments, the reaction of step vi) is performed at atemperature of about −100° C. to about −70° C. (e.g., about −90° C. toabout −80° C.).

In some embodiments, the organic solvent of step vii) is a halogenatedhydrocarbon. For example, the halogenated hydrocarbon of step vii) isdichloromethane or dichloroethane.

In some embodiments, the esterification reaction in step vii) isperformed at a temperature of about 0° C. to about 60° C. (e.g., about10° C. to about 40° C. or about 20° C. to about 30° C.).

In some embodiments, the compound of Formula 5 is selected from

1H-pyrrolo[2,3-b]pyridine (5a) or 5-chloro-1H-pyrrolo[2,3-b]pyridine(5b).

In some embodiments, the compound of Formula 6 is selected from

3-bromo-1H-pyrrolo[2,3-b]pyridine (6a) or3-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (6b); the compound of Formula7 is selected from

3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7a) or3-bromo-5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7b); the compound ofFormula 8 is selected from

1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8a) or5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8b); and thecompound of Formula 1 is selected from

3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a) or5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1b).

The present invention also provides a process for preparing a compoundof Formula 1:

or a pharmaceutically acceptable salt thereof, wherein R¹ is —H, —Cl, or—F; comprising the steps of: ivb) reacting a compound of Formula 5 withp-toluenesulfonyl chloride to generate a compound of Formula 9:

vb) reacting the compound of Formula 9 with N-bromosuccinimide togenerate a compound of Formula 7:

vi) reacting a compound of Formula 7 with triisopropyl borate, in thepresence of an organic solvent and a strong lithium base to generate acompound of Formula 8:

andvii) esterifying a compound of Formula 8 with pinacolate alcohol in anorganic solvent to generate a compound of Formula 1.

In some embodiments, the reaction of step ivb) is performed in thepresence of sodium hydride.

In some embodiments, the strong lithium base of step vi) is n-butyllithium.

In some embodiments, the reaction of step vi) is performed at atemperature of about −100° C. to about −70° C. (e.g., about −90° C. toabout −80° C.).

In some embodiments, the organic solvent of step vii) is a halogenatedhydrocarbon such as any of those halogenated hydrocarbons describedherein.

In some embodiments, the esterification reaction of step vii) isperformed at a temperature of about 0° C. to about 60° C. (e.g., about10° C. to about 40° C. or about 20° C. to about 30° C.).

In some embodiments, the compound of Formula 9 is selected from

1-tosyl-1H-pyrrolo[2,3-b]pyridine (9a) or5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (9b); the compound of Formula7 is selected from

3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7a) or3-bromo-5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7b); the compound ofFormula 8 is selected from

1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8a) or5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8b); and thecompound of Formula 1 is selected from

3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a) or5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1b).

The present invention also provides a process for preparing a compoundof Formula 2:

wherein R² is —H or —F; R³ is —Cl₄ aliphatic optionally substituted with1-5 occurrences of R⁵; R⁴ is —C₁₋₂ alkyl optionally substituted with 1-3occurrences of R⁵; or R³ and R⁴ are taken together to form a 3-7membered carbocyclic or heterocyclic saturated ring optionallysubstituted with 1-5 occurrences of R⁵; each R⁵ is independentlyselected from halogen, —OCH₃, —OH, —NO₂, —NH₂, —SH, —SCH₃, —NHCH₃, —CN,or unsubstituted —C₁₋₂ aliphatic, or two R⁵ groups, together with thecarbon to which they are attached, form a cyclopropyl ring; comprisingthe steps: viiia) reacting a compound of Formula 10, wherein R⁸ is a—C₁₋₄ alkyl, with a compound of Formula 11:

in the presence of an organic base and an organic solvent to generate amixture comprising a compound of Formula 12 and a compound of Formula13:

Some embodiments further comprising the steps of: ixa) deprotecting thecompound of Formula 12 and the compound of Formula 13 in the presence ofan inorganic acid to generate a mixture comprising a compound of Formula2 and a compound of Formula 14:

xa) reacting the mixture comprising the compound of Formula 2 and thecompound of Formula 14 with HCl in the presence of an organic solvent togenerate hydrochloride salts of the compound of Formula 2 and thecompound of Formula 14; and xia) recrystallizing the mixture comprisingthe HCl salts of the compound of Formula 2 and the compound of Formula14 to generate the hydrochloride salt of the compound of Formula 2.

In some embodiments, the compound of Formula 10 is selected from

(R)-tert-butyl 2-amino-2-methylbutanoate (10a) or tert-butyl2-amino-2-methylpropanoate (10b); the compound of Formula 11 is selectedfrom

2,4-dichloropyrimidine (11a) or 2,4-dichloro-5-fluoropyrimidine (11b);the compound of Formula 12 is selected from

(R)-tert-butyl 2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoate (12a)or tert-butyl2-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-methylpropanoate (12b); andthe compound of Formula 13 is selected from

(R)-tert-butyl 2-(4-chloropyrimidin-2-ylamino)-2-methylbutanoate (13a)or tert-butyl2-(4-chloro-5-fluoropyrimidin-2-ylamino)-2-methylpropanoate (13b).

In some embodiments, the compound of Formula 14 is selected from

(R)-2-(4-chloropyrimidin-2-ylamino)-2-methylbutanoic acid (14a) or2-(4-chloro-5-fluoropyrimidin-2-ylamino)-2-methylpropanoic acid (14b);and the compound of Formula 2 is selected from

(R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a) or2-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-methylpropanoic acid (2b).

The present invention also provides a process for preparing a compoundof Formula 2 comprising the steps:

wherein R² is —H or —F; R³ is —C₁₋₄ aliphatic optionally substitutedwith 1-5 occurrences of R⁵; R⁴ is —C₁₋₂ alkyl optionally substitutedwith 1-3 occurrences of R⁵; or R³ and R⁴ are taken together to form a3-7 membered carbocyclic or heterocyclic saturated ring optionallysubstituted with 1-5 occurrences of R⁵; each R⁵ is independentlyselected from halogen, —OCH₃, —OH, —NO₂, —NH₂, —SH, —SCH₃, —NHCH₃, —CN,or unsubstituted —C₁₋₂ aliphatic, or two R⁵ groups, together with thecarbon to which they are attached, form a cyclopropyl ring; comprisingthe steps: viiib) reacting a compound of Formula 11 with an acid salt ofa compound of Formula 15 in the presence of a solvent and a base togenerate the compound Formula 2

ixb) reacting the compound of Formula 2 with HCl to generate thehydrochloride salt of the compound of Formula 2.

In some embodiments, the acid salt of a compound of Formula 15 is ahydrochloride salt of the compound of Formula 15.

In some embodiments, the base of step viiib) is an inorganic baseselected from tripotassium phosphate, dipotassium hydrogen phosphate,dipotassium carbonate, disodium carbonate, trisodium phosphate, disodiumhydrogen phosphate, or any combination thereof.

In some embodiments, the solvent of step viiib) comprises water.

In some embodiments, the solvent of step viiib) further comprises analcohol selected from methanol, ethanol, propanol, iso-propanol,butanol, tert-butanol, or any combination thereof.

In some embodiments, the reaction of step viiib) is performed at atemperature of from about 70° C. to about 120° C. (e.g., from about 80°C. to about 100° C.).

In some embodiments, the compound of Formula 11 is selected from

2,4-dichloropyrimidine (11a) or 2,4-dichloro-5-fluoropyrimidine (11b);the compound of Formula 15 is selected from

D-isovaline (15a) or 2-amino-2-methylpropanoic acid (15b); and thecompound of Formula 2 is selected from

(R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a) or2-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-methylpropanoic acid (2b).

In some embodiments, the compound of Formula I is:

(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(Ia) or2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)propanamide(Ib).

The present invention also provides a process for preparing(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamideof Formula Ia:

or a pharmaceutically acceptable salt thereof, comprising the step of:i) reacting3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a) with the hydrochloride salt of(R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a),

in the presence of water, an organic solvent, an inorganic base, and apalladium catalyst to generate(R)-2-methyl-2-(2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)butanoicacid of Formula Ia.

Some embodiments further comprise the step of reacting

2,4-dichloropyrimidine (11a), and

D-isovaline (15a) to generate the hydrochloride salt of(R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid hydrochloride(2a)

The present invention also provides a process for preparing2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)propanamideof Formula Ib:

or a pharmaceutically acceptable salt thereof, comprising the step of:i) reacting5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1b) with the hydrochloride salt of2-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-methylpropanoic acidhydrochloride (2b),

in the presence of water, an organic solvent, an inorganic base, and apalladium catalyst to generate2-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-methylpropanoicacid of Formula Ib.

Some embodiments further comprise the step of reacting

2,4-dichloro-5-fluoropyrimidine (11b), and

2-amino-2-methylpropanoic acid (15b) to generate the hydrochloride saltof 2-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-methylpropanoic acid (2b)

The present invention also provides compounds useful as intermediates inthe processes of the present invention.

The present invention also provides a solid form of(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicacid (4a) designated as Form E. In some embodiments, solid Form E ischaracterized by one or more peaks corresponding to 2-theta valuesmeasured in degrees of 7.1±0.2, 8.2±0.2, 23.9±0.2, and 24.8±0.2 in anX-ray powder diffraction pattern.

The present invention also provides a solid form of(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicacid (4a) designated as Form B. In some embodiments, the solid Form B ischaracterized by one or more peaks corresponding to 2-theta valuesmeasured in degrees of 9.2±0.2, 18.1±0.2, 19.1±0.2, and 32.0±0.2 in anX-ray powder diffraction pattern. In other embodiments, solid Form B isfurther characterized by one or more peaks corresponding to 2-thetavalues measured in degrees of 21.4±0.2, 30.1±0.2, 29.9±0.2, and 26.1±0.2in an X-ray powder diffraction pattern.

The present invention also provides a solid form of(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(Ia) designated as Form A. In some embodiments, solid Form A ischaracterized by one or more peaks corresponding to 2-theta valuesmeasured in degrees of 23.7±0.2, 11.3±0.2, 19.3±0.2, and 15.4±0.2 in anX-ray powder diffraction pattern. In other embodiments, solid Form A isfurther characterized by one or more peaks corresponding to 2-thetavalues measured in degrees of 28.9±0.2 and 21.5±0.2 in an X-ray powderdiffraction pattern.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an XRPD pattern of Form E of Compound (4a).

FIG. 2 is an XRPD pattern of Form B of Compound (4a).

FIG. 3 is a solid state ¹H NMR spectrum for Form B of Compound (4a)according to procedure (H).

FIG. 4 is a DSC thermogram of Form B of Compound (4a).

FIG. 5 is a thermogravimetric trace of Form B of Compound (4a).

FIG. 6 is an XRPD pattern of Form A of Compound (Ia).

FIG. 7 is a DSC thermogram of Form A of Compound (Ia).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for preparing a compound ofFormula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is —H, —Cl or —F;

R² is —H or —F;

R³ is —C₁₋₄ aliphatic optionally substituted with 1-5 occurrences of R⁵;

R⁴ is —C₁₋₂ alkyl optionally substituted with 1-3 occurrences of R⁵; or

R³ and R⁴ are taken together to form a 3-7 membered carbocyclic orheterocyclic saturated ring optionally substituted with 1-5 occurrencesof R⁵;

each R⁵ is independently selected from halogen, —OCH₃, —OH, —NO₂, —NH₂,—SH, —SCH₃, —NHCH₃, —CN, or unsubstituted —C₁₋₂ aliphatic, or

-   -   two R⁵ groups, together with the carbon to which they are        attached, form a cyclopropyl ring;

R⁶ is —H or unsubstituted —C₁₋₂ alkyl; and

R⁷ is a —CH₂CR₃ or —(CH₂)₂CR₃ wherein each R is independently —H or —F;comprising the step of:

i) reacting a compound of Formula 1 with a hydrochloride (HCl) salt of acompound Formula 2

in the presence of water, an organic solvent, a base, and a transitionmetal (e.g., Pd) catalyst to generate a compound of Formula I.

As used herein, the following definitions shall apply unless otherwiseindicated.

I. DEFINITIONS

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75th Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry”,Thomas Sorrell, University Science Books, Sausalito: 1999, and “March'sAdvanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J.,John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention.

As used herein, the term “hydroxyl” or “hydroxy” refers to an —OHmoiety.

As used herein the term “aliphatic” encompasses the terms alkyl,alkenyl, alkynyl, each of which being optionally substituted as setforth below.

As used herein, an “alkyl” group refers to a saturated aliphatichydrocarbon group containing 1-12 (e.g., 1-8, 1-6, or 1-4) carbon atoms.An alkyl group can be straight or branched. Examples of alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or2-ethylhexyl. An alkyl group can be substituted (i.e., optionallysubstituted) with one or more substituents such as halo, phospho,cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic[e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl,alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl,(cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro,cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino,aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,heteroaralkylcarbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl,heterocycloalkylaminocarbonyl, arylaminocarbonyl, orheteroarylaminocarbonyl], amino [e.g., aliphaticamino,cycloaliphaticamino, or heterocycloaliphaticamino], sulfonyl [e.g.,aliphatic-SO₂—], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl,sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy,heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy,heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Withoutlimitation, some examples of substituted alkyls include carboxyalkyl(such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl),cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl,(alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as(alkyl-SO₂-amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl,or haloalkyl.

As used herein, an “alkenyl” group refers to an aliphatic carbon groupthat contains 2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and at leastone double bond. Like an alkyl group, an alkenyl group can be straightor branched. Examples of an alkenyl group include, but are not limitedto allyl, 1- or 2-isopropenyl, 2-butenyl, and 2-hexenyl. An alkenylgroup can be optionally substituted with one or more substituents suchas halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl],heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl],aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g.,(aliphatic)carbonyl, (cycloaliphatic)carbonyl, or(heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g.,(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl,cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g.,aliphaticamino, cycloaliphaticamino, heterocycloaliphaticamino, oraliphaticsulfonylamino], sulfonyl [e.g., alkyl-SO₂—,cycloaliphatic-SO₂—, or aryl-SO₂—], sulfinyl, sulfanyl, sulfoxy, urea,thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl,cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy,aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy, orhydroxy. Without limitation, some examples of substituted alkenylsinclude cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl,aralkenyl, (alkoxyaryl)alkenyl, (sulfonylamino)alkenyl (such as(alkyl-SO₂-amino)alkenyl), aminoalkenyl, amidoalkenyl,(cycloaliphatic)alkenyl, or haloalkenyl.

As used herein, an “alkynyl” group refers to an aliphatic carbon groupthat contains 2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and has atleast one triple bond. An alkynyl group can be straight or branched.Examples of an alkynyl group include, but are not limited to, propargyland butynyl. An alkynyl group can be optionally substituted with one ormore substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy,heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy,cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g., aliphaticsulfanylor cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsulfinyl orcycloaliphaticsulfinyl], sulfonyl [e.g., aliphatic-SO₂—,aliphaticamino-SO₂—, or cycloaliphatic-SO₂—], amido [e.g.,aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino,cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino,aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,(cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino,heteroarylcarbonylamino or heteroarylaminocarbonyl], urea, thiourea,sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic,heterocycloaliphatic, aryl, heteroaryl, acyl [e.g.,(cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl], amino[e.g., aliphaticamino], sulfoxy, oxo, carboxy, carbamoyl,(cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or (heteroaryl)alkoxy.

As used herein, an “amido” encompasses both “aminocarbonyl” and“carbonylamino”. These terms when used alone or in connection withanother group refer to an amido group such as —N(R^(X))—C(O)—R^(Y) or—C(O)—N(R^(X))₂, when used terminally, and —C(O)—N(R^(X))— or—N(R^(X))—C(O)— when used internally, wherein R^(X) and R^(Y) can bealiphatic, cycloaliphatic, aryl, araliphatic, heterocycloaliphatic,heteroaryl or heteroaraliphatic. Examples of amido groups includealkylamido (such as alkylcarbonylamino or alkylaminocarbonyl),(heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido,(heterocycloalkyl)alkylamido, arylamido, aralkylamido,(cycloalkyl)alkylamido, or cycloalkylamido.

As used herein, an “amino” group refers to —NR^(X)R^(Y) wherein each ofR^(X) and R^(Y) is independently hydrogen, aliphatic, cycloaliphatic,(cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic,(heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl,sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl,((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl,(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or(heteroaraliphatic)carbonyl, each of which being defined herein andbeing optionally substituted. Examples of amino groups includealkylamino, dialkylamino, or arylamino. When the term “amino” is not theterminal group (e.g., alkylcarbonylamino), it is represented by—NR^(X)—, where R^(X) has the same meaning as defined above.

As used herein, an “aryl” group used alone or as part of a larger moietyas in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refers to monocyclic(e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl,tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyltetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systemsin which the monocyclic ring system is aromatic or at least one of therings in a bicyclic or tricyclic ring system is aromatic. The bicyclicand tricyclic groups include benzofused 2-3 membered carbocyclic rings.For example, a benzofused group includes phenyl fused with two or moreC₄₋₈ carbocyclic moieties. An aryl is optionally substituted with one ormore substituents including aliphatic [e.g., alkyl, alkenyl, oralkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic;heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl;alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy;heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl;heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of abenzofused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl[e.g., (aliphatic)carbonyl; (cycloaliphatic)carbonyl;((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl;(heterocycloaliphatic)carbonyl;((heterocycloaliphatic)aliphatic)carbonyl; or(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphatic-SO₂— oramino-SO₂—]; sulfinyl [e.g., aliphatic-S(O)— or cycloaliphatic-S(O)—];sulfanyl [e.g., aliphatic-S—]; cyano; halo; hydroxy; mercapto; sulfoxy;urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, anaryl can be unsubstituted.

Non-limiting examples of substituted aryls include haloaryl [e.g.,mono-, di (such as p,m-dihaloaryl), and (trihalo)aryl]; (carboxy)aryl[e.g., (alkoxycarbonyl)aryl, ((aralkyl)carbonyloxy)aryl, and(alkoxycarbonyl)aryl]; (amido)aryl [e.g., (aminocarbonyl)aryl,(((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl,(arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl];aminoaryl [e.g., ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl];(cyanoalkyl)aryl; (alkoxy)aryl; (sulfamoyl)aryl [e.g.,(aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl;(hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl,((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl;(((alkylsulfonyl)amino)alkyl)aryl; ((heterocycloaliphatic)carbonyl)aryl;((alkylsulfonyl)alkyl)aryl; (cyanoalkyl)aryl; (hydroxyalkyl)aryl;(alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl;p-amino-m-alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl;or (m-(heterocycloaliphatic)-o-(alkyl))aryl.

As used herein, an “araliphatic” such as an “aralkyl” group refers to analiphatic group (e.g., a C₁₋₄ alkyl group) that is substituted with anaryl group. “Aliphatic,” “alkyl,” and “aryl” are defined herein. Anexample of an araliphatic such as an aralkyl group is benzyl.

As used herein, an “aralkyl” group refers to an alkyl group (e.g., aC₁₋₄ alkyl group) that is substituted with an aryl group. Both “alkyl”and “aryl” have been defined above. An example of an aralkyl group isbenzyl. An aralkyl is optionally substituted with one or moresubstituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl,including carboxyalkyl, hydroxyalkyl, or haloalkyl such astrifluoromethyl], cycloaliphatic [e.g., cycloalkyl or cycloalkenyl],(cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl,heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy,heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro,carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl,alkylcarbonylamino, cycloalkylcarbonylamino,(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, or heteroaralkylcarbonylamino], cyano, halo,hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, a “bicyclic ring system” includes 6-12 (e.g., 8-12 or 9,10, or 11) membered structures that form two rings, wherein the tworings have at least one atom in common (e.g., 2 atoms in common).Bicyclic ring systems include bicycloaliphatics (e.g., bicycloalkyl orbicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclicheteroaryls.

As used herein, a “cycloaliphatic” group encompasses a “cycloalkyl”group and a “cycloalkenyl” group, each of which being optionallysubstituted as set forth below.

As used herein, a “cycloalkyl” group refers to a saturated carbocyclicmono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbonatoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl,octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl,bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl,bicyclo[2.2.2]octyl, adamantyl, or((aminocarbonyl)cycloalkyl)cycloalkyl.

A “cycloalkenyl” group, as used herein, refers to a non-aromaticcarbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or moredouble bonds. Examples of cycloalkenyl groups include cyclopentenyl,1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl,octahydro-naphthyl, cyclohexenyl, bicyclo[2.2.2]octenyl, orbicyclo[3.3.1]nonenyl.

A cycloalkyl or cycloalkenyl group can be optionally substituted withone or more substituents such as phospho, aliphatic [e.g., alkyl,alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic,heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl,heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy,aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl,heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino,(cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino,(aryl)carbonylamino, (araliphatic)carbonylamino,(heterocycloaliphatic)carbonylamino,((heterocycloaliphatic)aliphatic)carbonylamino,(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro,carboxy [e.g., HOOC—, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g.,(cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl,(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,((heterocycloaliphatic)aliphatic)carbonyl, or(heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl[e.g., alkyl-SO₂— and aryl-SO₂—], sulfinyl [e.g., alkyl-S(O)—], sulfanyl[e.g., alkyl-S—], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, orcarbamoyl.

As used herein, the term “heterocycloaliphatic” encompassesheterocycloalkyl groups and heterocycloalkenyl groups, each of whichbeing optionally substituted as set forth below.

As used herein, a “heterocycloalkyl” group refers to a 3-10 memberedmono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- orbicyclic) saturated ring structure, in which one or more of the ringatoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examplesof a heterocycloalkyl group include piperidyl, piperazyl,tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl,1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl,octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl,octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl,octahydrobenzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl,1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and2,6-dioxa-tricyclo[3.3.1.0^(3,7)]nonyl. A monocyclic heterocycloalkylgroup can be fused with a phenyl moiety to form structures, such astetrahydroisoquinoline, which would be categorized as heteroaryls.

A “heterocycloalkenyl” group, as used herein, refers to a mono- orbicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ringstructure having one or more double bonds, and wherein one or more ofthe ring atoms is a heteroatom (e.g., N, O, or S). Monocyclic andbicyclic heterocycloaliphatics are numbered according to standardchemical nomenclature.

A heterocycloalkyl or heterocycloalkenyl group can be optionallysubstituted with one or more substituents such as phospho, aliphatic[e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic,(cycloaliphatic)aliphatic, heterocycloaliphatic,(heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy,(cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy,(araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino,amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino,((cycloaliphatic) aliphatic)carbonylamino, (aryl)carbonylamino,(araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino,((heterocycloaliphatic) aliphatic)carbonylamino,(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro,carboxy [e.g., HOOC—, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g.,(cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl,(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,((heterocycloaliphatic)aliphatic)carbonyl, or(heteroaraliphatic)carbonyl], nitro, cyano, halo, hydroxy, mercapto,sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl [e.g.,alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

A “heteroaryl” group, as used herein, refers to a monocyclic, bicyclic,or tricyclic ring system having 4 to 15 ring atoms wherein one or moreof the ring atoms is a heteroatom (e.g., N, O, S, or combinationsthereof) and in which the monocyclic ring system is aromatic or at leastone of the rings in the bicyclic or tricyclic ring systems is aromatic.A heteroaryl group includes a benzofused ring system having 2 to 3rings. For example, a benzofused group includes benzo fused with one ortwo 4 to 8 membered heterocycloaliphatic moieties (e.g., indolizyl,indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl,benzo[b]thiophene-yl, quinolinyl, or isoquinolinyl). Some examples ofheteroaryl are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl,thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl,isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine,dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl,indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl,quinazolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl,4H-quinolizyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.

Without limitation, monocyclic heteroaryls include furyl, thiophene-yl,2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl,pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl.Monocyclic heteroaryls are numbered according to standard chemicalnomenclature.

Without limitation, bicyclic heteroaryls include indolizyl, indolyl,isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl,quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl,benzo[b]furyl, bexo[b]thiophenyl, indazolyl, benzimidazyl,benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl,phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl.Bicyclic heteroaryls are numbered according to standard chemicalnomenclature.

A heteroaryl is optionally substituted with one or more substituentssuch as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic;(cycloaliphatic)aliphatic; heterocycloaliphatic;(heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;(cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy;(araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo(on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic ortricyclic heteroaryl); carboxy; amido; acyl [e.g., aliphaticcarbonyl;(cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl;(araliphatic)carbonyl; (heterocycloaliphatic)carbonyl;((heterocycloaliphatic)aliphatic)carbonyl; or(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphaticsulfonyl oraminosulfonyl]; sulfinyl [e.g., aliphaticsulfinyl]; sulfanyl [e.g.,aliphaticsulfanyl]; nitro; cyano; halo; hydroxy; mercapto; sulfoxy;urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, aheteroaryl can be unsubstituted.

Non-limiting examples of substituted heteroaryls include(halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl];(carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl]; cyanoheteroaryl;aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl and((dialkyl)amino)heteroaryl]; (amido)heteroaryl [e.g.,aminocarbonylheteroaryl, ((alkylcarbonyl)amino)heteroaryl,((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl,(((heteroaryl)amino)carbonyl)heteroaryl,((heterocycloaliphatic)carbonyl)heteroaryl, and((alkylcarbonyl)amino)heteroaryl]; (cyanoalkyl)heteroaryl;(alkoxy)heteroaryl; (sulfamoyl)heteroaryl [e.g.,(aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g.,(alkylsulfonyl)heteroaryl]; (hydroxyalkyl)heteroaryl;(alkoxyalkyl)heteroaryl; (hydroxy)heteroaryl;((carboxy)alkyl)heteroaryl; (((dialkyl)amino)alkyl]heteroaryl;(heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl;(nitroalkyl)heteroaryl; (((alkylsulfonyl)amino)alkyl)heteroaryl;((alkylsulfonyl)alkyl)heteroaryl; (cyanoalkyl)heteroaryl;(acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl]; (alkyl)heteroaryl;or (haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryl].

A “heteroaraliphatic (such as a heteroaralkyl group) as used herein,refers to an aliphatic group (e.g., a C₁₋₄ alkyl group) that issubstituted with a heteroaryl group. “Aliphatic,” “alkyl,” and“heteroaryl” have been defined above.

A “heteroaralkyl” group, as used herein, refers to an alkyl group (e.g.,a C₁₋₄ alkyl group) that is substituted with a heteroaryl group. Both“alkyl” and “heteroaryl” have been defined above. A heteroaralkyl isoptionally substituted with one or more substituents such as alkyl(including carboxyalkyl, hydroxyalkyl, and haloalkyl such astrifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy,cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl,alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino,cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino,arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo,hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, “cyclic moiety” and “cyclic group” refer to mono-, bi-,and tri-cyclic ring systems including cycloaliphatic,heterocycloaliphatic, aryl, or heteroaryl, each of which has beenpreviously defined.

As used herein, a “bridged bicyclic ring system” refers to a bicyclicheterocyclicalipahtic ring system or bicyclic cycloaliphatic ring systemin which the rings are bridged. Examples of bridged bicyclic ringsystems include, but are not limited to, adamantanyl, norbornanyl,bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl,bicyclo[3.3.2]decyl, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl,3-azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.0^(3,7)]nonyl. Abridged bicyclic ring system can be optionally substituted with one ormore substituents such as alkyl (including carboxyalkyl, hydroxyalkyl,and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl,heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy,heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro,carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl,alkylcarbonylamino, cycloalkylcarbonylamino,(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo,hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, an “acyl” group refers to a formyl group or R^(X)—C(O)—(such as alkyl-C(O)—, also referred to as “alkylcarbonyl”) where R^(X)and “alkyl” have been defined previously. Acetyl and pivaloyl areexamples of acyl groups.

As used herein, an “aroyl” or “heteroaroyl” refers to an aryl-C(O)— or aheteroaryl-C(O)—. The aryl and heteroaryl portion of the aroyl orheteroaroyl is optionally substituted as previously defined.

As used herein, an “alkoxy” group refers to an alkyl-O— group where“alkyl” has been defined previously.

As used herein, a “carbamoyl” group refers to a group having thestructure —O—CO—NR^(X)R^(Y) or —NR^(X)—CO—O—R^(Z), wherein R^(X) andR^(Y) have been defined above and R^(Z) can be aliphatic, aryl,araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.

As used herein, a “carboxy” group refers to —COOH, —COOR^(X), —OC(O)H,—OC(O)R^(X), when used as a terminal group; or —OC(O)— or —C(O)O— whenused as an internal group.

As used herein, a “haloaliphatic” group refers to an aliphatic groupsubstituted with 1-3 halogen. For instance, the term haloalkyl includesthe group —CF₃.

As used herein, a “mercapto” group refers to —SH.

As used herein, a “sulfo” group refers to —SO₃H or —SO₃R^(X) when usedterminally or —S(O)₃— when used internally.

As used herein, a “sulfamide” group refers to the structure—NR^(X)—S(O)₂—NR^(Y)R^(Z) when used terminally and —NR^(X)—S(O)₂—NR^(Y)—when used internally, wherein R^(X), R^(Y), and R^(Z) have been definedabove.

As used herein, a “sulfamoyl” group refers to the structure—O—S(O)₂—NR^(Y)R^(Z) wherein

R^(Y) and R^(Z) have been defined above.

As used herein, a “sulfonamide” group refers to the structure—S(O)₂—NR^(X)R^(Y) or —NR^(X)—S(O)₂—R^(Z) when used terminally; or—S(O)₂—NR^(X)— or —NR^(X)—S(O)₂— when used internally, wherein R^(X),R^(Y), and R^(Z) are defined above.

As used herein a “sulfanyl” group refers to —S—R^(X) when usedterminally and —S— when used internally, wherein R^(X) has been definedabove. Examples of sulfanyls include aliphatic-S—, cycloaliphatic-S—,aryl-S—, or the like.

As used herein a “sulfinyl” group refers to —S(O)—R^(X) when usedterminally and —S(O)—when used internally, wherein R^(X) has beendefined above. Exemplary sulfinyl groups include aliphatic-S(O)—,aryl-S(O)—, (cycloaliphatic(aliphatic))-S(O)—, cycloalkyl-S(O)—,heterocycloaliphatic-S(O)—, heteroaryl-S(O)—, or the like.

As used herein, a “sulfonyl” group refers to —S(O)₂—R^(X) when usedterminally and —S(O)₂— when used internally, wherein R^(X) has beendefined above. Exemplary sulfonyl groups include aliphatic-S(O)₂—,aryl-S(O)₂—, (cycloaliphatic(aliphatic))-S(O)₂—, cycloaliphatic-S(O)₂—,heterocycloaliphatic-S(O)₂—, heteroaryl-S(O)₂—,(cycloaliphatic(amido(aliphatic)))-S(O)₂— or the like.

As used herein, a “sulfoxy” group refers to —O—S(O)—R^(X) or—S(O)—O—R^(X), when used terminally and —O—S(O)— or —S(O)—O— when usedinternally, where R^(X) has been defined above.

As used herein, a “halogen” or “halo” group refers to fluorine,chlorine, bromine or iodine.

As used herein, an “alkoxycarbonyl,” which is encompassed by the termcarboxy, used alone or in connection with another group refers to agroup such as alkyl-O—C(O)—.

As used herein, an “alkoxyalkyl” refers to an alkyl group such asalkyl-O-alkyl-, wherein alkyl has been defined above.

As used herein, a “carbonyl” refer to —C(O)—.

As used herein, an “oxo” refers to ═O.

As used herein, the term “phospho” refers to phosphinates andphosphonates. Examples of phosphinates and phosphonates include—P(O)(R^(P))₂, wherein R^(P) is aliphatic, alkoxy, aryloxy,heteroaryloxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy aryl,heteroaryl, cycloaliphatic or amino.

As used herein, an “aminoalkyl” refers to the structure(R^(X))₂N-alkyl-.

As used herein, a “cyanoalkyl” refers to the structure (NC)-alkyl-.

As used herein, a “urea” group refers to the structure—NR^(X)—CO—NR^(Y)R^(Z) and a “thiourea” group refers to the structure—NR^(X)—CS—NR^(Y)R^(Z) when used terminally and —NR^(X)—CO—NR^(Y)— or—NR^(X)—CS—NR^(Y)— when used internally, wherein R^(X), R^(Y), and R^(Z)have been defined above.

As used herein, a “guanidine” group refers to the structure—N═C(N(R^(X)R^(Y)))N(R^(X)R^(Y)) or —NR^(X)—C(═NR^(X))NR^(X)R^(Y)wherein R^(X) and R^(Y) have been defined above.

As used herein, the term “amidino” group refers to the structure—C═(NR^(X))N(R^(X)R^(Y)) wherein R^(X) and R^(Y) have been definedabove.

In general, the term “vicinal” refers to the placement of substituentson a group that includes two or more carbon atoms, wherein thesubstituents are attached to adjacent carbon atoms.

In general, the term “geminal” refers to the placement of substituentson a group that includes two or more carbon atoms, wherein thesubstituents are attached to the same carbon atom.

The terms “terminally” and “internally” refer to the location of a groupwithin a substituent. A group is terminal when the group is present atthe end of the substituent not further bonded to the rest of thechemical structure. Carboxyalkyl, i.e., R^(X)O(O)C-alkyl is an exampleof a carboxy group used terminally. A group is internal when the groupis present in the middle of a substituent of the chemical structure.Alkylcarboxy (e.g., alkyl-C(O)O— or alkyl-OC(O)—) and alkylcarboxyaryl(e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxygroups used internally.

As used herein, an “aliphatic chain” refers to a branched or straightaliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups).A straight aliphatic chain has the structure —[CH₂]_(v)—, where v is1-12. A branched aliphatic chain is a straight aliphatic chain that issubstituted with one or more aliphatic groups. A branched aliphaticchain has the structure —[CQQ]_(v)- where Q is independently a hydrogenor an aliphatic group; however, Q shall be an aliphatic group in atleast one instance. The term aliphatic chain includes alkyl chains,alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynylare defined above.

In general, the term “substituted,” whether preceded by the term“optionally” or not, refers to the replacement of hydrogen atoms in agiven structure with the radical of a specified substituent. Specificsubstituents are described above in the definitions and below in thedescription of compounds and examples thereof. Unless otherwiseindicated, an optionally substituted group can have a substituent ateach substitutable position of the group, and when more than oneposition in any given structure can be substituted with more than onesubstituent selected from a specified group, the substituent can beeither the same or different at every position. A ring substituent, suchas a heterocycloalkyl, can be bound to another ring, such as acycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings shareone common atom. As one of ordinary skill in the art will recognize,combinations of substituents envisioned by this invention are thosecombinations that result in the formation of stable or chemicallyfeasible compounds.

The phrase “stable or chemically feasible,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

As used herein, an “effective amount” is defined as the amount requiredto confer a therapeutic effect on the treated patient, and is typicallydetermined based on age, surface area, weight, and condition of thepatient. The interrelationship of dosages for animals and humans (basedon milligrams per meter squared of body surface) is described byFreireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surfacearea may be approximately determined from height and weight of thepatient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley,N.Y., 537 (1970). As used herein, “patient” refers to a mammal,including a human.

Chemical structures and nomenclature are derived from ChemDraw, version11.0.1, Cambridge, Mass.

It is noted that the use of the descriptors “first”, “second”, “third”,or the like is used to differentiate separate elements (e.g., solvents,reaction steps, processes, reagents, or the like) and may or may notrefer to the relative order or relative chronology of the elementsdescribed.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersible products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described herein, “protecting group” refers to a moiety orfunctionality that is introduced into a molecule by chemicalmodification of a functional group in order to obtain chemoselectivityin a subsequent chemical reaction. Standard protecting groups areprovided in Wuts and Greene: “Greene's Protective Groups in OrganicSynthesis” 4th Ed, Wuts, P. G. M. and Greene, T. W., Wiley-Interscience,New York: 2006, which is incorporated herein by reference.

Examples of nitrogen protecting groups include acyl, aroyl, or carbamylgroups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl,2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl,4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl and chiral auxiliariessuch as protected or unprotected D, L or D, L-amino acids such asalanine, leucine, phenylalanine and the like; sulfonyl groups such asbenzenesulfonyl, p-toluenesulfonyl and the like; carbamate groups suchas benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike, arylalkyl groups such as benzyl, triphenylmethyl, benzyloxymethyland the like and silyl groups such as trimethylsilyl and the like.Preferred N-protecting groups are benzenesulfonylchloridep-toluenesulfonyl and the like, including, but not limited to, tosyl.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools, probes inbiological assays, or JAK inhibitors with improved therapeutic profile.

As used herein, the term “solvent” also includes mixtures of solvents.

II. SYNTHETIC PROCESSES

The present invention provides a process for preparing a compound ofFormula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is —H, —Cl or —F;

R² is —H or —F;

R³ is —C₁₋₄ aliphatic optionally substituted with 1-5 occurrences of R⁵;

R⁴ is —C₁₋₂alkyl optionally substituted with 1-3 occurrences of R⁵; or

R³ and R⁴ are taken together to form a 3-7 membered carbocyclic orheterocyclic saturated ring optionally substituted with 1-5 occurrencesof R⁵;

each R⁵ is independently selected from halogen, —OCH₃, —OH, —NO₂, —NH₂,—SH, —SCH₃, —NHCH₃, —CN, or unsubstituted —C₁₂ aliphatic, or

-   -   two R⁵ groups, together with the carbon to which they are        attached, form a cyclopropyl ring;

R⁶ is —H or unsubstituted —C₁₋₂alkyl; and

R⁷ is a —CH₂CR₃ or —(CH₂)₂CR₃ wherein each R is independently —H or —F;

comprising the step of:

i) reacting a compound of Formula 1 with a compound Formula 2 or ahydrochloride salt of a compound of Formula 2

in the presence of water, an organic solvent, a base, and a transitionmetal (e.g., Pd) catalyst to generate a compound of Formula I.

The present invention provides a process for preparing a compound ofFormula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is —H, —Cl or —F;

R² is —H or —F;

R³ is —C₁₋₄ aliphatic optionally substituted with 1-5 occurrences of R⁵;

R⁴ is —C₁₋₂ alkyl optionally substituted with 1-3 occurrences of R⁵; or

R³ and R⁴ are taken together to form a 3-7 membered carbocyclic orheterocyclic saturated ring optionally substituted with 1-5 occurrencesof R⁵;

each R⁵ is independently selected from halogen, —OCH₃, —OH, —NO₂, —NH₂,—SH, —SCH₃, —NHCH₃, —CN, or unsubstituted —C₁₋₂ aliphatic, or

-   -   two R⁵ groups, together with the carbon to which they are        attached, form a cyclopropyl ring;

R⁶ is —H or unsubstituted —C₁₋₂ alkyl; and

R⁷ is a —CH₂CR₃ or —(CH₂)₂CR₃ wherein each R is independently —H or —F;comprising the steps of:

i) reacting a compound of Formula 1 with a hydrochloride salt of acompound Formula 2

in the presence of water, an organic solvent, a base, and a transitionmetal catalyst to generate a compound of Formula 3

ii) deprotecting the compound of Formula 3 to generate a compound ofFormula 4,

and

iii) reacting the compound of Formula 4 with HNR⁶R⁷ in the presence of acoupling agent and an organic solvent to generate the compound ofFormula I.

The present invention provides a process for preparing(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamideof Formula Ia:

comprising the step of:

i) reacting3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a) and (R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acidhydrochloride (2a)

in the presence of water, an organic solvent, an inorganic base, and atransition metal catalyst to generate(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamideof Formula Ia.

The present invention also provides a process for preparing(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamideof Formula Ia:

comprising the steps of:

i) reacting3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a) with the hydrochloride (HCl) salt of(R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid hydrochloride(2a),

in the presence of water, an organic solvent, an inorganic base, and atransition metal (e.g., Pd) catalyst to generate(R)-2-methyl-2-(2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)butanoicacid of Formula 3a,

ii) deprotecting the compound of Formula 3a under basic conditions togenerate(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicof Formula 4a,

and

iii) reacting the compound of Formula 4a with 2,2,2-trifluoroethylamine(CF₃CH₂NH₂); in the presence of a coupling agent and an organic solventto generate the compound of Formula Ia.

The present invention provides for a process for preparing2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)propanamideof Formula Ib:

comprising the steps of:

i) reacting5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1b) with 2-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-methylpropanoicacid hydrochloride (2b),

in the presence of water, an organic solvent, an inorganic base, and atransition metal catalyst to generate2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)propanamideof Formula Ib.

The present invention also provides for a process for preparing2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)propanamideof Formula Ib:

comprising the steps of:

i) reacting or coupling5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1b) with 2-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-methylpropanoicacid hydrochloride (2b),

in the presence of water, an organic solvent, an inorganic base, and atransition metal catalyst to generate2-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-methylpropanoicacid of Formula 3b,

ii) deprotecting the compound of Formula 3b under basic conditions togenerate2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-methylpropanoicacid of Formula 4b

and

iii) reacting the compound of Formula 4b with 2,2,2-trifluoroethylamine(CF₃CH₂NH₂), in the presence of a coupling agent and an organic solventto generate the compound of Formula Ib.

A. Step i)

In some embodiments, the organic solvent of step i) above is an aproticsolvent. For example, the aprotic solvent of step i) comprisesacetonitrile, toluene, N,N-dimethylformamide, N,N-dimethylacetamide,acetone, methyl tert-butyl ether, or any combination thereof. In otherexamples, the aprotic solvent is acetonitrile.

In some embodiments, the organic solvent of step i) is a protic solvent.For example, the protic solvent comprises ethanol, methanol,isopropanol, or any combination thereof. In other examples, the proticsolvent comprises ethanol, isopropanol, or any combination thereof. Forinstance, the protic solvent comprises isopropanol.

In some embodiments, the base of step i) is an inorganic base. Examplesof inorganic bases include tripotassium phosphate, dipotassium hydrogenphosphate, dipotassium carbonate, disodium carbonate, trisodiumphosphate, or disodium hydrogen phosphate. In some embodiments, theinorganic base is tripotassium phosphate, dipotassium hydrogenphosphate, trisodium phosphate, or disodium hydrogen phosphate. In otherembodiments, the inorganic base is tripotassium phosphate. Otherexamples of inorganic bases include alkali metal hydroxides such asNaOH, KOH, or any combination thereof.

In some embodiments, the transition metal catalyst in step i) is apalladium catalyst. Examples of palladium catalysts includepalladium(II)acetate, tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0), or any combination thereof. Insome embodiments, the palladium-based catalyst is palladium(II)acetate.Other examples of palladium catalysts include

or any combination thereof.

In some embodiments, the palladium catalyst is formed in situ.

In some embodiments, the water, organic solvent, and inorganic base ofstep i) combine to comprise a biphasic mixture. In other embodiments, instep i) where the palladium catalyst is formed in situ, this mixtureadditionally comprises a phosphine ligand. Examples of phosphine ligandsinclude a triarylphosphine ligand or a trialkylphosphine ligand. In someembodiments, the phosphine ligand is a triarylphosphine ligand. Forexample, the triarylphosphine ligand is triphenylphosphine.

In some embodiments, step i) further comprises adding a catalyst (e.g.,a palladium catalyst as described above) and compound of Formula 1 afterthe reaction has run for a period of more than 1 hour (e.g., about 2hours or more or about 5 hours).

In some embodiments, step i) further includes adding a catalyst (e.g., apalladium catalyst as described above) and compound of Formula 1 afterthe reaction is about 86% complete.

In some embodiments, the reaction of step i) is performed at atemperature between about 50° C. and about 110° C. For example, thereaction of step i) is performed at a temperature between about 60° C.and about 95° C. In other embodiments, the reaction of step i) isperformed at a temperature between about 70° C. and about 80° C.

In some embodiments, step i) is performed with agitation. For example,the reaction is performed in a vessel containing a stir bar thatagitates the reaction mixture.

In some embodiments, the reaction of step i) is completed in about 17hours.

In some embodiments, the reaction of step i) is about 86% complete in aperiod of about 5 hours.

In other embodiments, the reaction of step i) is about 99% complete in aperiod of about 17 hours.

B. Step ii)

In some embodiments, step ii) comprises deprotecting the compound ofFormula 3 in the presence of a base. In some examples, the basecomprises an inorganic base such as an alkali metal hydroxide. Examplesof alkali metal hydroxides include NaOH, KOH, or any combinationthereof. In other embodiments, step ii) comprises deprotecting thecompound of Formula 3 in the presence of KOH.

In some embodiments, the alkali-metal hydroxide base has a concentrationof about 2N to about 6N. In other embodiments, the alkali-metalhydroxide base has a concentration of about 4N. For example, in someembodiments, the concentration of potassium hydroxide is about 3N toabout 5N. In other embodiments, the concentration of potassium hydroxideis about 4N.

In some embodiments, the deprotection reaction in step ii) is performedat a temperature between about 60° C. and about 110° C. For example thedeprotection reaction in step ii) is performed at a temperature betweenabout 65° C. and about 95° C. In other examples, the deprotectionreaction in step ii) is performed at a temperature between about 70° C.and about 80° C.

C. Step iii)

In some embodiments, the coupling agent of step iii) is propylphosphonicanhydride.

In some embodiments, the organic solvent of step iii) comprises ahalogenated hydrocarbon, an alkyl substituted tetrahydrofuran, or anycombination thereof. For example, the organic solvent comprises an alkylsubstituted tetrahydrofuran comprising 2-methyltetrahydrofuran(2-MeTHF).

In some embodiments, the organic solvent of step iii) is a halogenatedhydrocarbon. Examples of halogenated hydrocarbons includedichloromethane or dichloroethane. In some embodiments, the halogenatedhydrocarbon is dichloromethane.

In some embodiments, the reaction of step iii) is performed in thepresence of a base. In some examples, the base is an organic base. Insome embodiments, the organic base of step iii) above is a tertiaryamine. For example, the organic base in step iii) isN,N-diisopropylethylamine, trimethylamine, or any combination thereof.

In some embodiments, the reaction of step iii) is performed at atemperature of about 40° C. or less. For example, the reaction of stepiii) is performed at a temperature of about 35° C. In still otherembodiments, the reaction of step iii) is performed at a temperature ofabout 25° C.

In some embodiments, HNR⁶R⁷ in step iii) is CF₃(CH₂)₂NH₂ or CF₃CH₂NH₂.In other embodiments, HNR⁶R⁷ in step iii) is CH₃(CH₂)₂NH₂ or CH₃CH₂NH₂.In still other embodiments, HNR⁶R⁷ in step iii) is CF₃CH₂NH₂ orCH₃CH₂NH₂. In further embodiments, HNR⁶R⁷ in step iii) is CF₃CH₂NH₂.

In some embodiments, the process further comprises the additional stepof purifying a compound of Formula 4. For example, after step ii) andbefore step iii), step iiia) comprises crystallizing a compound ofFormula 4. In some embodiments, step iiia) is repeated.

In some embodiments, the crystallization in step iiia) is performedunder basic conditions. In other embodiments, the crystallization instep iiia) is performed under acidic conditions. In still otherembodiments, the crystallization is performed in basic conditionsfollowed by a subsequent crystallization, which is performed underacidic conditions, or vice versa.

In some embodiments, the process further comprises the additional stepsafter step ii) and before step iii) of:

iiia) adding an organic solvent, adjusting the pH of the mixture to <1.0using concentrated HCl; and

iiid) drying the solids.

In some embodiments, the process further comprises the additional stepsafter step ii) and before step iii) of:

iiia) adding an organic solvent, adjusting the pH of the mixture to <1.0using concentrated HCl;

iiib) adding charcoal and filtering;

iiic) repeating step iiib) two times; and

iiid) drying the solids.

In some embodiments, the organic solvent in step iiia) is isopropylacetate.

D. Additional Steps

Some embodiments further comprise comprising the steps of:

iva) reacting a compound of Formula 5 with bromine in an organic solventto generate a compound of Formula 6:

va) reacting the compound of Formula 6 with p-toluenesulfonyl chlorideto generate a compound of Formula 7:

vi) reacting the compound of Formula 7 with triisopropyl borate, in thepresence of an organic solvent and a strong lithium base to generate acompound of Formula 8:

and

vii) esterifying a compound of Formula 8 with pinacolate alcohol in anorganic solvent to generate a compound of Formula 1.

Some alternative embodiments further comprise the steps of:

ivb) reacting a compound of Formula 5 with p-toluenesulfonyl chloride togenerate a compound of Formula 9:

vb) reacting the compound of Formula 9 with N-bromosuccinimide togenerate a compound of Formula 7:

vi) reacting the compound of Formula 7 with triisopropyl borate, in thepresence of an organic solvent and a strong lithium base to generate acompound of Formula 8:

and

vii) esterifying the compound of Formula 8 with pinacolate alcohol in anorganic solvent to generate a compound of Formula 1.

The present invention also provides for a process for preparing acompound of Formula 1

wherein

R¹ is —H, —Cl, or —F;

comprising the steps of:

iva) reacting a compound of Formula 5 with bromine (Br₂) in an organicsolvent to generate a compound of Formula 6:

va) reacting the compound of Formula 6 in an organic solvent with anN-protecting group (e.g., p-toluenesulfonyl chloride) to generate acompound of Formula 7

where PG is a protecting group (e.g., Ts):

in particular reacting a compound of Formula 6 in an organic solventwith p-toluenesulfonyl chloride to generate a compound of Formula 7:

vi) reacting the compound of Formula 7 in an organic solvent withtriisopropyl borate, in the presence of a strong lithium base togenerate a compound of Formula 8:

and

iv) esterifying the compound of Formula 8 with pinacolate alcohol in anorganic solvent to generate a compound of Formula 1:

The present invention provides for a process for preparing a compound ofFormula Ia:

comprising the steps of:

iva) reacting 1H-pyrrolo[2,3-b]pyridine (5a) with bromine (Br₂) in anorganic solvent to generate 3-bromo-1H-pyrrolo[2,3-b]pyridine (6a)

va) reacting 3-bromo-1H-pyrrolo[2,3-b]pyridine (6a) in an organicsolvent with p-toluenesulfonyl chloride to generate3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7a)

vi) reacting 3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7a) in anorganic solvent with triisopropyl borate in the presence of a stronglithium base to generate 1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronicacid (8a)

and

vii) esterifying 1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8a)with pinacolate alcohol in an organic solvent to generate3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a).

The present invention provides for a process for preparing a compound ofFormula 1b:

comprising the steps of:

iva) reacting 5-chloro-1H-pyrrolo[2,3-b]pyridine (5b) with bromine (Br₂)in an organic solvent to generate5-chloro-3-bromo-1H-pyrrolo[2,3-b]pyridine (6b)

va) reacting 5-chloro-3-bromo-1H-pyrrolo[2,3-b]pyridine (6b) in anorganic solvent with p-toluenesulfonyl chloride to generate5-chloro-3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7b)

vi) reacting 5-chloro-3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7b) inan organic solvent with triisopropyl borate in the presence of a stronglithium base to generate5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8b)

and

vii) esterifying 1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8b)with pinacolate alcohol in an organic solvent to generate5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1b).

In some embodiments, the organic solvent in step iva) is an aproticsolvent. For example, the aprotic solvent is dimethylformamide.

In some embodiments, the reaction in step iva) is performed at atemperature of about −5° C. to about 30° C. In other embodiments, thereaction is performed at a temperature of about 0° C. to about 10° C.

In some embodiments, the organic solvent in step va) above is an aproticsolvent. In other embodiments, the aprotic solvent is tetrahudrofuran.

In some embodiments, step va) is performed in the presence of sodiumhydride.

In some embodiments, the reaction in step va) is performed at atemperature of about 0° C. to about 30° C. In some embodiments, thereaction is performed at a temperature of about 5° C. to about 25° C. Inother embodiments, the reaction is performed at a temperature of about10° C. to about 20° C.

In some embodiments, the strong lithium base in step vi) is n-butyllithium.

In some embodiments, the reaction in step vi) is performed at atemperature of about −100° C. to about −70° C. In other embodiments, thereaction is performed at a temperature of about −90° C. to about −80° C.

In some embodiments, the organic solvent in step vii) above is ahalogenated hydrocarbon. Examples of halogenated hydrocarbons includedichloromethane or dichloroethane. In some embodiments, the halogenatedhydrocarbon is dichloromethane.

In some embodiments, the esterification reaction in step vii) isperformed at a temperature of about 0° C. to about 60° C. In otherembodiments, the esterification reaction in step vii) is performed at atemperature of about 10° C. to about 40° C. In still other embodiments,the esterification reaction in step vii) is performed at a temperatureof about 20° C. to about 30° C.

Some embodiments further comprise comprising the step of:

viiia) reacting a compound of Formula 10, wherein R⁸ is a —C₁₋₄ alkyl(e.g., tert-butyl), with a compound of Formula 11

in the presence of an organic base and an organic solvent to generate amixture comprising a compound of Formula 12 and a compound of Formula13:

Some embodiments further comprise the steps of:

ixa) deprotecting the compound of Formula 12 and the compound of Formula13 in the presence of an inorganic acid to generate a mixture comprisingthe compound of Formula 2 and a compound of Formula 14:

xa) reacting the mixture comprising the compound of Formula 2 and thecompound of Formula 14 with HCl in the presence of an organic solvent togenerate the hydrochloride salts of the compound of Formula 2 and thecompound of Formula 14; and

xia) recrystallizing the mixture of the hydrochloride salts of thecompound of Formula 2 and the compound of Formula 14 to generate thehydrochloride salt of the compound of Formula 2.

Some alternative embodiments further comprise the steps of:

viiib) reacting a compound of Formula 11 with an acid salt of a compoundof Formula 15 in the presence of a solvent and a base to generate thecompound Formula 2

and

ixb) reacting the compound of Formula 2 with an acid (e.g., HCl) togenerate the acid (e.g., hydrochloride) salt of the compound of Formula2.

In some embodiments, the base of step viiib) is an inorganic baseselected from tripotassium phosphate, dipotassium hydrogen phosphate,dipotassium carbonate, disodium carbonate, trisodium phosphate, disodiumhydrogen phosphate, or any combination thereof.

In some embodiments, the solvent of step viiib) comprises water.

In some embodiments, the solvent of step viiib) further comprises analcohol selected from methanol, ethanol, propanol, iso-propanol,butanol, tert-butanol, or any combination thereof.

In some embodiments, the reaction of step viiib) is performed at atemperature of from about 70° C. to about 120° C. In some embodiments,the reaction of step viiib) is performed at a temperature of from about80° C. to about 100° C.

The present invention also provides a process for preparing an HCl saltof a compound of Formula 2

wherein

R² is —H or —F;

R³ is —C₁₋₄ aliphatic optionally substituted with 1-5 occurrences of R⁵;

R⁴ is —C₁₋₂ alkyl; or

R³ and R⁴ are taken together to form a 3-7 membered carbocyclic orheterocyclic saturated ring optionally substituted with 1-5 occurrencesof R⁵;

each R⁵ is independently selected from halogen, —OCH₃, —OH, —NO₂, —NH₂,—SH, —SCH₃, —NHCH₃, —CN or unsubstituted —C₁₋₂ aliphatic, or two R⁵groups, together with the carbon to which they are attached, form acyclopropyl ring;

comprising:

viiia) reacting a compound of Formula 10, wherein R⁸ is a —C₁₋₄ alkyl(e.g., tert-butyl), with a compound of Formula 11

in the presence of an organic base and an organic solvent to generate amixture comprising a compound of Formula 12 and a compound of Formula13:

ixa) deprotecting the compound of Formula 12 and the compound of Formula13 in the presence of an inorganic acid to generate a mixture comprisingthe compound of Formula 2 and a compound of Formula 14:

xa) reacting the mixture comprising the compound of Formula 2 and thecompound of Formula 14 with HCl in the presence of an organic solvent togenerate the hydrochloride salts of the compound of Formula 2 and thecompound of Formula 14; and

xia) recrystallizing the mixture of the hydrochloride salts of thecompound of Formula 2 and the compound of Formula 14 to generate thehydrochloride salt of the compound of Formula 2.

The present invention also provides for a process for preparing an HClsalt of a compound of Formula 2

wherein

R² is —H or —F;

R³ is —C₁₋₄ aliphatic optionally substituted with 1-5 occurrences of R⁵;

R⁴ is —C₁₋₂alkyl; or

R³ and R⁴ are taken together to form a 3-7 membered carbocyclic orheterocyclic saturated ring optionally substituted with 1-5 occurrencesof R⁵;

each R⁵ is independently selected from halogen, —OCH₃, —OH, —NO₂, —NH₂,—SH, —SCH₃, —NHCH₃, —CN or unsubstituted —C₁₋₂ aliphatic, or

-   -   two R⁵ groups, together with the carbon to which they are        attached, form a cyclopropyl ring;

comprising:

viiib) reacting a compound of Formula 11 with a compound of Formula 15under coupling conditions to generate a compound of Formula 2:

and

ixb) reacting the compound of Formula 2 with HCl to generate thehydrochloride salt of the compound of Formula 2.

In some embodiments, the compound of Formula 11 reacts with the compoundof Formula 15 under in the presence of a base and an organic solvent.

In other embodiments, the base comprises a carbonate of an alkali earthmetal or a hydroxide of an alkali earth metal. For instance, the basecomprises potassium carbonate.

In other embodiments, the solvent comprises an alcohol (e.g., methanol,ethanol, propanol, or any combination thereof).

In some embodiments, the HCl salt of the compound of Formula 2 is acompound of Formula 2a:

the compound of Formula 11 is 2,4-dichloropyrimidine (11a), and thecompound of Formula 15 is D-isovaline (15a).

In some embodiments, the HCl salt of the compound of Formula 2 is acompound of Formula 2b:

the compound of Formula 11 is 2,4-dichloro-5-fluoropyrimidine (11b), andthe compound of Formula 15 is 2-amino-2-methylpropanoic acid (15b).

The present invention provides for a process for preparing a compound ofFormula 2a:

comprising the steps of:

xii) reacting a compound of Formula (16)

with 2,4-dichloropyrimidine (11a) in the presence of an inorganic acidand an organic solvent to generate a mixture comprising a compound ofFormula (2a) and a compound of Formula (14a); and

xiii) recrystallizing the mixture comprising the compound of Formula(2a) and the compound of Formula (14a) from an organic solvent togenerate the compound of Formula (2a).

The present invention provides for a process for preparing a compound ofFormula 2b:

comprising the steps of:

xii) reacting a compound of Formula (17)

with 5-fluoro-2,4-dichloropyrimidine (11b) in the presence of aninorganic acid and an organic solvent to generate a compound of Formula(2b) and a compound of Formula (14b); and

xiii) recrystallizing the mixture of the compound of Formula (2b) andthe compound of Formula (14b) from an organic solvent to generate thecompound of Formula (2b).

In some embodiments, the organic solvent in step xii) above is dioxane.

In some embodiments, the inorganic acid in step xii) is hydrochloricacid (HCl).

In some embodiments, the reaction in step xii) is performed for betweenabout 6 to about 24 hours.

In some embodiments, the organic solvent in step xiii) is a mixture ofethyl acetate and isopropyl acetate.

In some embodiments, the compounds of Formula 2, Formula 2a and Formula2b may also be another salt form instead of the HCl salt, including butnot limited to an HBr salt or a sulfate salt.

In other embodiments, the compounds of Formula 2, Formula 2a, andFormula 2b may also be the free carboxylic acid form instead of a saltform.

The present invention provides for a process for preparing a compound ofFormula 2a:

comprising:

reacting 2,4-dichloropyrimidine (11a) with D-isovaline (15a) undercoupling conditions to generate the compound of Formula (2a).

In some embodiments, the compound of Formula 11a reacts with thecompound of Formula 15a under in the presence of a base and an organicsolvent.

In other embodiments, the base comprises a carbonate of an alkali earthmetal or a hydroxide of an alkali earth metal. For instance, the basecomprises potassium carbonate.

In other embodiments, the solvent comprises an alcohol (e.g., methanol,ethanol, propanol, or any combination thereof).

The present invention provides for a process for preparing a compound ofFormula 2b:

comprising:

reacting 2,4-dichloro-5-fluoropyrimidine (11b) with2-amino-2-methylpropanoic acid (15b) under coupling conditions to thecompound of Formula (2b).

In some embodiments, the compound of Formula 11b reacts with thecompound of Formula 15b under in the presence of a base and an organicsolvent.

In other embodiments, the base comprises a carbonate of an alkali earthmetal or a hydroxide of an alkali earth metal. For instance, the basecomprises potassium carbonate.

In other embodiments, the solvent comprises an alcohol (e.g., methanol,ethanol, propanol, or any combination thereof).

In some embodiments of the above processes, the compound of Formula Iis:

(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(Ia);

the compound of Formula 1 is:

3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a);

the HCl salt of the compound of Formula 2 is:

(R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid hydrochloride(2a); the compound of Formula 3 is:

(R)-2-methyl-2-(2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)butanoicacid (3a);

the compound of Formula 4 is:

(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicacid (4a); and HNR⁶R⁷ is 2,2,2-trifluoroethylamine (CF₃CH₂NH₂).

In some embodiments, the compound of Formula 11 is2,4-dichloropyrimidine (11a) and the compound of Formula 15 isD-isovaline (15a).

In other embodiments of the above processes, Formula I is:

2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)propanamide(Ib);

the compound of Formula 1 is:

5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1b);

the HCl salt of the compound of Formula 2 is:

2-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-methylpropanoic acidhydrochloride (2b); the compound of Formula 3 is:

2-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-methylpropanoicacid (3b);

the compound of Formula 4 is:

2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-methylpropanoicacid (4b); and HNR⁶R⁷ is 2,2,2-trifluoroethylamine (CF₃CH₂NH₂).

In some embodiments, the compound of Formula 11 is2,4-dichloro-5-fluoropyrimidine

(11b) and the compound of Formula 15 is 2-amino-2-methylpropanoic acid(15b).

In some embodiments, this invention provides a process for producing apharmaceutically acceptable salt of compounds of Formulae I, Ia or Ib,which further comprise the step of making a salt of a compound ofFormulae I, Ia or Ib.

The present invention also provides a process for preparing a compoundof Formula I:

wherein:

R¹ is —H, —Cl or —F;

R² is —H or —F;

R³ is —C₁₋₄ aliphatic optionally substituted with 1-5 occurrences of R⁵;

R⁴ is —C₁₋₂alkyl; or

R³ and R⁴ are taken together to form a 3-7 membered carbocyclic orheterocyclic saturated ring optionally substituted with 1-5 occurrencesof R⁵;

each R⁵ is independently selected from halogen, —OCH₃, —OH, —NO₂, —NH₂,—SH, —SCH₃, —NHCH₃, —CN, or unsubstituted —C₁₋₂ aliphatic, or

-   -   two R⁵ groups, together with the carbon to which they are        attached, form a cyclopropyl ring;

R⁶ is —H or unsubstituted —C₁₋₂ alkyl; and

R⁷ is a —CH₂CR₃ or —(CH₂)₂CR₃ wherein each R is independently —H or —F;comprising the steps of:

iva) reacting a compound of Formula 5 with bromine (Br₂) in an organicsolvent to generate a compound of Formula 6:

va) reacting a compound of Formula 6 in an organic solvent withp-toluenesulfonyl chloride to generate a compound of Formula 7:

vi) reacting a compound of Formula 7 in an organic solvent withtriisopropyl borate in the presence of a strong lithium base to generatea compound of Formula 8

vii) esterifying the compound of Formula 8 with pinacolate alcohol in anorganic solvent to generate a compound of Formula 1:

viiic) reacting a compound of Formula 10, wherein R⁸ is C₁₋₄ alkyl, withan inorganic base to generate a salt of the compound of Formula 10:

ixc) reacting the salt of the compound of Formula 10 with a compound ofFormula 11 in the presence of an organic base and an organic solvent togenerate a mixture of compounds of Formulae 12 and 13:

ixa) deprotecting the compound of Formula 12 and the compound of Formula13 with an inorganic acid in an organic solvent to generate a mixturecomprising compounds 2 and 14:

xia) recrystallizing the mixture of compounds comprising Formulae 2 and14 from an organic solvent to generate a compound of Formula 2;

i) reacting the compound of Formula 1 and the hydrochloride salt of acompound of Formula 2

in the presence of water, an organic solvent, an inorganic base, and atransition metal catalyst to generate a compound of Formula 3,

ii) deprotecting the compound of Formula 3 under basic conditions togenerate a compound of Formula 4

and

iii) reacting the compound of Formula 4 with HNR⁶R⁷ in the presence of acoupling agent and an organic solvent to generate the compound ofFormula I.

The present invention also provides a process for preparing a compoundof Formula I:

wherein:

R¹ is —H, —Cl or —F;

R² is —H or —F;

R³ is —C₁₋₄ aliphatic optionally substituted with 1-5 occurrences of R⁵;

R⁴ is —C₁₋₂alkyl; or

R³ and R⁴ are taken together to form a 3-7 membered carbocyclic orheterocyclic saturated ring optionally substituted with 1-5 occurrencesof R⁵;

each R⁵ is independently selected from halogen, —OCH₃, —OH, —NO₂, —NH₂,—SH, —SCH₃, —NHCH₃, —CN, or unsubstituted —C₁₂ aliphatic, or

-   -   two R⁵ groups, together with the carbon to which they are        attached, form a cyclopropyl ring;

R⁶ is —H or unsubstituted —C₁₋₂ alkyl; and

R⁷ is a —CH₂CR₃ or —(CH₂)₂CR₃ wherein each R is independently —H or —F;comprising the steps of:

ivb) reacting a compound of Formula 5 with p-toluenesulfonyl chloride inthe presence of an organic solvent to generate a compound of Formula 9:

vb) reacting the compound of Formula 9 with N-bromosuccinimide togenerate a compound of Formula 7:

vi) reacting the compound of Formula 7 with triisopropyl borate, in thepresence of an organic solvent and a strong lithium base to generate acompound of Formula 8:

vii) esterifying the compound of Formula 8 with pinacolate alcohol in anorganic solvent to generate a compound of Formula 1

viiib) reacting a compound of Formula 11 with a compound of Formula 15under coupling conditions to generate a compound of Formula 2:

ixb) reacting the compound of Formula 2 with HCl to generate thehydrochloride salt of the compound of Formula 2;

i) reacting the compound of Formula 1 and the HCl salt of the compoundof Formula 2

in the presence of water, an organic solvent, an inorganic base, and atransition metal catalyst to generate a compound of Formula 3,

ii) deprotecting the compound of Formula 3 under basic conditions togenerate a compound of Formula 4

and

iii) reacting the compound of Formula 4 with HNR⁶R⁷ in the presence of acoupling agent and an organic solvent to generate the compound ofFormula I.

In some embodiments, the organic solvent in step i) is an aproticsolvent.

In other embodiments, the aprotic solvent of step i) is acetonitrile,toluene, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, ormethyl tert-butyl ether.

In some embodiments, the organic solvent in step i) is a protic solvent.

In other embodiments, the protic solvent of step i) is ethanol,methanol, or isopropanol.

In some embodiments, the base in step i) is an inorganic base.

In other embodiments, the inorganic base of step i) is tripotassiumphosphate, dipotassium hydrogen phosphate, dipotassium carbonate,disodium carbonate, trisodium phosphate, or disodium hydrogen phosphate.

In other embodiments, the inorganic base of step i) is an alkali metalhydroxide such as NaOH, KOH, or any combination thereof.

In some embodiments, the transition metal catalyst in step i) is apalladium-based catalyst.

In other embodiments, the palladium-based catalyst ispalladium(II)acetate, tetrakis(triphenylphosphine)palladium(0) ortris(dibenzylideneacetone)dipalladium(0).

In still other embodiments, the palladium-based catalyst ispalladium(II)acetate.

In some embodiments, the palladium catalyst is selected from:

or any combination thereof.

In some embodiments, the reaction of step i) is performed in thepresence of a phosphine ligand.

In further embodiments, the phosphine ligand is a triarylphosphineligand or a trialkylphosphine ligand.

In still further embodiments, the triarylphosphine ligand istriphenylphosphine.

In some embodiments, the reaction of step i) is performed at atemperature between about 50° C. to about 110° C.

In other embodiments, the reaction of step i) is performed at atemperature between about 60° C. to about 95° C.

In still other embodiments, the reaction of step i) is performed at atemperature between about 70° C. to about 80° C.

In some embodiments, step i) is performed with agitation. For example,the reaction is performed in a vessel containing a stir bar thatagitates the reaction mixture.

In some embodiments, the reaction of step i) occurs in about 17 hours.

In some embodiments, the reaction is about 86% complete in about 5hours.

In other embodiments, the reaction is about 99% complete in about 17hours.

The present invention provides a process for preparing(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamideof Formula Ia:

comprising the steps of:

iva) reacting 1H-pyrrolo[2,3-b]pyridine (5a) with bromine (Br₂) in thepresence of an organic solvent to generate3-bromo-1H-pyrrolo[2,3-b]pyridine (6a)

va) reacting 3-bromo-1H-pyrrolo[2,3-b]pyridine (6a) in an organicsolvent with p-toluenesulfonyl chloride to generate3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7a)

vi) reacting 3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7a) withtriisopropyl borate in the presence of a strong lithium base in anorganic solvent to generate 1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronicacid (8a)

vii) esterifying 1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8a)with pinacolate alcohol in an organic solvent to generate3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a):

viiib) reacting 2,4-dichloropyrimidine (11a) with a hydrochloride saltof D-isovaline (15a) under coupling condition to generate a compound ofFormula 2a

ixb) reacting the compound of Formula 2a with HCl to generate thehydrochloride salt of the compound of Formula 2a;

i) reacting the compound of Formula Ia with the compound of Formula 2awith in the presence of water, an organic solvent, an inorganic base,and a transition metal catalyst to generate a compound of Formula 3a,

ii) deprotecting the compound of Formula 3a under basic conditions togenerate a compound of Formula 4a

and

iii) reacting the compound of Formula 4a with 2,2,2-trifluoroethylaminein the presence of a coupling agent and an organic solvent to generatethe compound of Formula Ia.

The present invention provides a process for preparing(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamideof Formula Ia:

comprising the steps of:

ivb) reacting 1H-pyrrolo[2,3-b]pyridine (5a) with p-toluenesulfonylchloride in the presence of an organic solvent to generate1-tosyl-1H-pyrrolo[2,3-b]pyridine (9a)

vb) reacting 1-tosyl-1H-pyrrolo[2,3-b]pyridine (9a) in an organicsolvent with N-bromosuccinimide to generate3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7a)

vi) reacting 3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7a) withtriisopropyl borate in the presence of a strong lithium base in anorganic solvent to generate 1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronicacid (8a)

vii) esterifying 1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8a)with pinacolate alcohol in an organic solvent to generate3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a):

viiib) reacting 2,4-dichloropyrimidine (11a) with a hydrochloride saltof D-isovaline (15a) under coupling condition to generate a compound ofFormula 2a

ixb) reacting the compound of Formula 2a with HCl to generate thehydrochloride salt of the compound of Formula 2a;

i) reacting the compound of Formula Ia with the compound of Formula 2awith in the presence of water, an organic solvent, an inorganic base,and a transition metal catalyst to generate a compound of Formula 3a,

ii) deprotecting the compound of Formula 3a under basic conditions togenerate a compound of Formula 4a

and

iii) reacting the compound of Formula 4a with 2,2,2-trifluoroethylaminein the presence of a coupling agent and an organic solvent to generatethe compound of Formula Ia.

The present invention provides a process for preparing(2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)propanamideof Formula Ib:

comprising the steps of:

iva) reacting 5-chloro-1H-pyrrolo[2,3-b]pyridine (5b) with bromine (Br₂)in an organic solvent to generate5-chloro-3-bromo-1H-pyrrolo[2,3-b]pyridine (6b)

va) reacting 5-chloro-3-bromo-1H-pyrrolo[2,3-b]pyridine (6b) in anorganic solvent with p-toluenesulfonyl chloride to generate5-chloro-3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7b)

vi) reacting 5-chloro-3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7b)with triisopropyl borate in the presence of a strong lithium base in anorganic solvent to generate5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8b)

vii) esterifying 1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8b)with pinacolate alcohol in an organic solvent to generate5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1b):

viiib) reacting 2,4-dichloro-5-fluoropyrimidine (11b) with2-amino-2-methylpropanoic acid (15b) under coupling condition togenerate (2b)

ixb) reacting the compound of Formula 2b with HCl to generate thehydrochloride salt of the compound of Formula 2b;

i) reacting the compound of Formula (2b) with the compound of Formula(1b) in the presence of water, an organic solvent, an inorganic base,and a transition metal catalyst to generate a compound of Formula 3b,

ii) deprotecting the compound of Formula 3b under basic conditions togenerate a compound of Formula 4b

and

iii) reacting the compound of Formula 4b with CF₃(CH₂)NH₂, in thepresence of a coupling agent and an organic solvent to generate thecompound of Formula Ib.

The present invention provides a process for preparing(2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)propanamideof Formula Ib:

comprising the steps of:

ivb) reacting 5-chloro-1H-pyrrolo[2,3-b]pyridine (5b) withp-toluenesulfonyl chloride in an organic solvent to generate5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (9b)

vb) reacting 5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (9b) in anorganic solvent with N-bromosuccinimide to generate5-chloro-3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7b)

vi) reacting 5-chloro-3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7b)with triisopropyl borate in the presence of a strong lithium base in anorganic solvent to generate5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8b)

vii) esterifying 1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8b)with pinacolate alcohol in an organic solvent to generate5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1b):

viiib) reacting 2,4-dichloro-5-fluoropyrimidine (11b) with2-amino-2-methylpropanoic acid (15b) under coupling condition togenerate (2b)

ixb) reacting the compound of Formula 2b with HCl to generate thehydrochloride salt of the compound of Formula 2b;

i) reacting the compound of Formula (2b) with the compound of Formula(1b) in the presence of water, an organic solvent, an inorganic base,and a transition metal catalyst to generate a compound of Formula 3b,

ii) deprotecting the compound of Formula 3b under basic conditions togenerate a compound of Formula 4b

and

iii) reacting the compound of Formula 4b with CF₃(CH₂)NH₂, in thepresence of a coupling agent and an organic solvent to generate thecompound of Formula Ib.

In some embodiments of the above processes, the compound of Formula Iis:

(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(Ia);

Formula 1 is:

3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a);

the HCl salt of Formula 2 is:

(R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid hydrochloride(2a); Formula 3 is:

(R)-2-methyl-2-(2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)butanoicacid (3a);

Formula 4 is:

(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicacid (4a); and

HNR⁶R⁷ is 2,2,2-trifluoroethylamine (CF₃CH₂NH₂).

In other embodiments of the above processes, the compound of Formula Iis:

2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)propanamide(Ib);

Formula 1 is:

5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1b);

the HCl salt of Formula 2 is:

2-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-methylpropanoic acidhydrochloride (2b); Formula 3 is:

2-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-methylpropanoicacid (3b);

Formula 4 is:

2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-methylpropanoicacid (4b); and

HNR⁶R⁷ is 2,2,2-trifluoroethylamine (CF₃CH₂NH₂).

In some embodiments, the organic solvent in step i) is an aproticsolvent.

In other embodiments, the aprotic solvent is acetonitrile, toluene,N,N-dimethylformamide, N,N-dimethylacetamide, acetone, or methyltert-butyl ether.

In still other embodiments, the aprotic solvent is acetonitrile.

In some embodiments, the organic solvent in step i) is a protic solvent.

In other embodiments, the protic solvent is ethanol, methanol, orisopropanol.

In still other embodiments, the protic solvent is ethanol orisopropanol.

In some embodiments, the base in step i) is an inorganic base.

In other embodiments, the inorganic base is tripotassium phosphate,dipotassium hydrogen phosphate, dipotassium carbonate, disodiumcarbonate, trisodium phosphate, or disodium hydrogen phosphate.

In still other embodiments, the inorganic base is tripotassiumphosphate, dipotassium hydrogen phosphate, trisodium phosphate, ordisodium hydrogen phosphate.

In further embodiments, the inorganic base is tripotassium phosphate.

In some embodiments, the transition metal catalyst in step i) is apalladium-based catalyst.

In other embodiments, the palladium-based catalyst ispalladium(II)acetate, tetrakis(triphenylphosphine)palladium(0) ortris(dibenzylideneacetone)dipalladium(0).

In still other embodiments, the palladium-based catalyst ispalladium(II)acetate.

In some embodiments, the palladium catalyst is selected from

or any combination thereof.

In some embodiments, the reaction of step i) is performed in thepresence of a phosphine ligand.

In other embodiments, the phosphine ligand is a triarylphosphine ligandor a trialkylphosphine ligand.

In still other embodiments, the phosphine ligand triarylphosphine ligandis triphenylphosphine.

In some embodiments, the reaction of step i) is performed at betweenabout 50° C. to about 110° C.

In other embodiments, the reaction of step i) is performed at betweenabout 60° C. to about 95° C.

In still other embodiments, the reaction of step i) is performed atbetween about 70° C. to about 80° C.

In some embodiments, step i) is carried out with agitation.

In some embodiments, the reaction of step i) occurs in about 17 hours.

In some embodiments, the reaction is about 86% complete in about 5hours.

In other embodiments, the reaction is about 99% complete in about 17hours.

In some embodiments, an alkali-metal hydroxide base is present in stepiii).

In other embodiments, the alkali-metal hydroxide base is selected fromsodium hydroxide or potassium hydroxide.

In still other embodiments, the alkali-metal hydroxide base is potassiumhydroxide.

In some embodiments, the alkali-metal hydroxide base is about 2N toabout 4N.

In other embodiments, the alkali-metal hydroxide base is about 4N.

In some embodiments, the concentration of potassium hydroxide is about2N to about 4N.

In other embodiments, the concentration of potassium hydroxide is about4N.

In some embodiments, the deprotection reaction in step iii) is performedat between about 60° C. to about 110° C. In other embodiments, thedeprotection reaction is performed between about 65° C. to about 95° C.

In still other embodiments, the deprotection reaction is performedbetween about 70° C. to about 80° C.

In still other embodiments, the coupling agent of step iii) ispropylphosphonic anhydride.

In some embodiments, the organic solvent of step iii) is a halogenatedhydrocarbon or alkyl-substituted THF (e.g., 2-MeTHF).

In other embodiments, the halogenated hydrocarbon is dichloromethane ordichloroethane.

In some embodiments, step i) includes an additional step of addingcatalyst and compound of Formula 1 after the reaction has run for about5 hours.

In some embodiments, step i) includes an additional step of addingcatalyst and compound of Formula 1 after the coupling reaction is about86% complete.

In some embodiments, the compounds of Formula 2, Formula 2a and Formula2b may also be another salt form instead of the HCl salt, including butnot limited to an HBr salt or a sulfate salt.

In other embodiments, the compounds of Formula 2, Formula 2a and Formula2b may also be the free carboxylic acid form instead of a salt form.

In other embodiments, in a compound of any Formulae I, 2, 3 or 4, R³ andR⁴ are taken together to form a ring selected from:

wherein one or more carbon atoms in said ring are optionally andindependently replaced by N, O or S.

In another embodiment, in a compound of any Formulae I, 2, 3, or 4, R³and R⁴ are:

In a further embodiment, R³ and R⁴ are:

In yet a further embodiment, R³ and R⁴ are:

In still a further embodiment, R³ and R⁴ are:

III. PROCESSES AND INTERMEDIATES

The following definitions describe terms and abbreviations used herein:

Ac acetylBu butylEt ethylPh phenylMe methylTHF tetrahydrofuranDCM dichloromethaneCH₂Cl₂ dichloromethaneEtOAc ethyl acetateCH₃CN acetonitrileEtOH ethanolMeOH methanolMTBE methyl tert-butyl ether

DMF N,N-dimethylformamide DMA N,N-dimethylacetamide

DMSO dimethyl sulfoxideHOAc acetic acidTFA trifluoroacetic acidEt₃N triethylamineDIPEA diisopropylethylamineDIEA diisopropylethylamineK₂CO₃ dipotassium carbonateNa₂CO₃ disodium carbonateNaOH sodium hydroxideK₃PO₄ tripotassium phosphateHPLC high performance liquid chromtagraphyHr or h hoursatm atmospheresrt or RT room temperatureHCl hydrochloric acidHBr hydrobromic acidH₂O waterNaOAc sodium acetateH₂SO₄ sulfuric acidN₂ nitrogen gasH₂ hydrogen gasBr₂ brominen-BuLi n-butyl lithiumPd(OAc)₂ palladium(II)acetatePPh₃ triphenylphosphinerpm revolutions per minuteEquiv. equivalentsTs tosylIPA isopropyl alcohol

As used herein, other abbreviations, symbols and conventions areconsistent with those used in the contemporary scientific literature.See, e.g., Janet S. Dodd, ed., The ACS Style Guide: A Manual for Authorsand Editors, 2nd Ed., Washington, D.C.: American Chemical Society, 1997,herein incorporated in its entirety by reference.

In one embodiment, the invention provides a process and intermediatesfor preparing a compound of Formula I as outlined in Scheme I.

In Scheme I, a compound of Formula 1 is coupled with a compound ofFormula 2 via a palladium catalyzed cross coupling reaction to generatea compound of Formula 3. The compound of Formula 3 is deprotected (e.g.,via treatment with a base) to generate a compound of Formula 4. Thecompound of Formula 4 is then coupled with an amine having the formulaHNR⁶R⁷ in the presence of a coupling reagent to generate the compound ofFormula I, wherein R¹, R², R³, R⁴, R⁶, and R⁷, are defined herein.

In Scheme Ia, a compound of Formula 11 is reacted with a compound ofFormula 15 under coupling conditions to generate the HCl salt of thecompound of Formula 2. In Scheme Ia, radicals R², R³, and R⁴ are asdefined herein.

In Scheme Ib, a tosylate salt of a compound of Formula 10 is prepared bymixing a compound of Formula i in an organic solvent (e.g., ethylacetate) with a solution of an inorganic base (e.g., an alkali metalbase such as but not limited to NaOH). Preparation of a mixture of acompound of Formula 12 and a compound of Formula 13 is achieved byreacting a compound of Formula 10 with an organic base (e.g.,diisopropylethylamine (DIEA)) in an organic solvent (e.g., isopropylalcohol) at a suitable temperature (e.g., between about 80° C. and about110° C.) for a suitable time period (e.g., for between about 30 andabout 80 hours). An HCl salt of a compound of Formula 2 and a compoundof Formula 14 are prepared by adding an inorganic acid (e.g., HCl) to amixture of the compound of Formula 12 and the compound of Formula 13,adjusting the pH of the solution to a suitable value (e.g., 3), thenadding additional inorganic acid (e.g., HCl) in an organic solvent(e.g., ethyl acetate). The compound of Formula 2 is purified byrecrystallization of the mixture of the compound of Formula 2 and thecompound of Formula 14 from an organic solvent (e.g., a mixture of ethylacetate and isopropyl alcohol). In Scheme Ib, radicals R², R³, and R⁴are as defined herein.

In Scheme Ic, a compound of Formula 10a is prepared by mixing a compoundof Formula ia (Nagase & Company, Ltd., made according to the processoutlined in US2007/161624) in an organic solvent (e.g., ethyl acetate)with a solution of an inorganic base (e.g., an alkali metal base such asNaOH). Preparation of a mixture of (R)-tert-butyl2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoate (12a) and(R)-tert-butyl 2-(4-chloropyrimidin-2-ylamino)-2-methylbutanoate (13a)is achieved by reacting a compound of Formula 10a with a compound ofFormula 11a in the presence of an organic base (e.g.,diisopropylethylamine (DIEA)) in an organic solvent (e.g., isopropylalcohol) at a suitable temperature (e.g., about 95° C.) for a suitabletime period (e.g., for about 40 hours).(R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a) and(R)-2-(4-chloropyrimidin-2-ylamino)-2-methylbutanoic acid (14a) areprepared by adding inorganic acid (e.g., HCl) to a mixture of(R)-tert-butyl 2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoate (12a)and (R)-tert-butyl 2-(4-chloropyrimidin-2-ylamino)-2-methylbutanoate(13a), adjusting the pH of the solution to a suitable value (e.g., pH3), then adding additional inorganic acid (e.g., HCl) in a suitableorganic solvent (e.g., ethyl acetate).(R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a) ispurified by recrystallization of the mixture of(R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a) and(R)-2-(4-chloropyrimidin-2-ylamino)-2-methylbutanoic acid (14a) from anorganic solvent (e.g., a mixture of ethyl acetate and isopropylalcohol).

In another embodiment, the invention provides a process andintermediates to prepare a compound of Formula 1 as outlined below inScheme II.

In Scheme II, a compound of Formula 6 is prepared by the addition of amixture of a compound of Formula 5 in a solvent (e.g., DMF) to a mixtureof Br₂ in a solvent (e.g., DMF) at a suitable temperature (e.g., about0° C. to about 10° C.). Preparation of a compound of Formula 7 isachieved by mixing a compound of Formula 6 in an aprotic solvent (e.g.,THF) with NaH while cooling to a suitable temperature (e.g., about 10°C. to about 20° C.) and then adding 4-methybenzenesulfonylchloride(TsCl) while maintaining the temperature at (e.g., about 10° C. to about20° C.). A compound of Formula 8 is then prepared following Scheme II bymixing triisopropyl borate, a compound of Formula 7 and a strong lithiumbase (e.g., n-butyl lithium (n-BuLi)) in an organic solvent (e.g., THF)at a suitable temperature (e.g., about −90 to about −80° C.).Preparation of a compound of Formula 1 is achieved by adding pinacolatealcohol to a compound of Formula 8 in an organic solvent (e.g.,dichloromethane) at a suitable temperature (e.g., about 20 to about 30°C.). In Scheme II, radical R¹ is as defined herein.

In another embodiment, the invention provides a process andintermediates to prepare a compound of Formula Ia as described below inScheme IIa.

In Scheme IIa, 3-bromo-1H-pyrrolo[2,3-b]pyridine (6a) is prepared by theaddition of a mixture of 1H-pyrrolo[2,3-b]pyridine (5a) in a solvent(e.g., DMF) to a mixture of Br₂ in a solvent (e.g., DMF) at a suitabletemperature (e.g., about 0° C. to about 10° C.). Preparation of3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7a) is achieved by mixing3-bromo-1H-pyrrolo[2,3-b]pyridine (6a) in an aprotic solvent (e.g., THF)with NaH while cooling to a suitable temperature (e.g., about 10° C. toabout 20° C.) and then adding p-toluenesulfonyl chloride whilemaintaining the temperature at a suitable temperature (e.g., about 10°C. to about 20° C.). 1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid(8a) is then prepared according to Scheme IIa by mixing triisopropylborate, 3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7a) and n-butyllithium (n-BuLi) in an organic solvent (e.g., THF) at a suitabletemperature (e.g., about −90 to about −80° C.). Preparation of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a) is achieved by adding pinacolate alcohol to1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8a) in an organicsolvent (e.g., dichloromethane) at a suitable temperature (e.g., about20° C. to about 30° C.).

In Scheme IIb, 1-tosyl-1H-pyrrolo[2,3-b]pyridine (9a) is prepared byreaction of 1H-pyrrolo[2,3-b]pyridine (5a) with TsCl in the presence ofNaH. Preparation of 3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7a) isachieved by brominating 1-tosyl-1H-pyrrolo[2,3-b]pyridine (9a) withN-bromosuccinimide (NBS). 1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronicacid (8a) is then prepared according to Scheme IIb by mixingtriisopropyl borate, 3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7a) andn-butyl lithium (n-BuLi) in an organic solvent (e.g., THF) at a suitabletemperature (e.g., about −90 to about −80° C.). Preparation of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a) is achieved by adding pinacolate alcohol to1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8a) in an organicsolvent (e.g., dichloromethane) at a suitable temperature (e.g., about20° C. to about 30° C.).

In Scheme IIc, Compound 1a is coupled with Compound 2a via a palladiumcatalyzed cross coupling reaction to generate Compound 3a. Compound 3ais deprotected (e.g., via treatment with a base) to generate Compound4a. Compound 4a is then coupled with 2,2,2-trifluoroethylamine in thepresence of a coupling reagent to generate Compound 1a.

Scheme III is useful for preparing [¹³C,¹⁵N]-enriched compounds ofFormula I. [¹³C,¹⁵N]-enriched pyrimidine-2,4(1H,3H)-dione (iiia)([¹³C,¹⁵N]-enriched labeled uracil), is reacted with POCl₃ in thepresence of a base, PhNEt₂, under heat to generate [¹³C,¹⁵N]-enriched2,4-dichloropyrimidine (11a*). [¹³C,¹⁵N]-enriched 2,4-dichloropyrimidine(11a*) is coupled with2-amino-2-methyl-N-(2,2,2-trifluoroethyl)propanamide (iiib) under basicconditions to generate [¹³C,¹⁵N]-enriched(R)-2-((2-chloropyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(iiic). And, [¹³C,¹⁵N]-enriched(R)-2-((2-chloropyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(iiic) is coupled with3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a) via a transition metal (i.e. Pd(P(Ph)₃)₄) catalyzed cross-couplingreaction to generate [¹³C,¹⁵N]-enriched(R)-2-methyl-2-((2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)butanamide(iiid), and deprotecting [¹³C,¹⁵N]-enriched(R)-2-methyl-2-((2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)butanamide(iiid) to generate [¹³C,¹⁵N]-enriched(R)-2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(Ia*).

In Scheme IV, [¹⁴C]-enriched urea is reacted with propiolic acid togenerate [¹⁴C]-enriched uracil, which is reacted with POCl₃ and PCl₅ togenerate [¹⁴C]-enriched 2,4-dichloropyrimidine (11a**). [¹⁴C]-enriched2,4-dichloropyrimidine is coupled with the compound of Formula 15 togenerate the [¹⁴C]-enriched compound of Formula 2**. And, the[¹⁴C]-enriched compound of Formula 2** is reacted with the compound ofFormula 1 to generate the compound of Formula I**.

The schemes above are useful for generating novel intermediates that areuseful for generating compounds of Formula I.

The present invention also provides a solid form of(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicacid (4a) designated as Form E. In some embodiments, solid Form E ischaracterized by one or more peaks corresponding to 2-theta valuesmeasured in degrees of 7.1±0.2, 8.2±0.2, 23.9±0.2, and 24.8±0.2 in anX-ray powder diffraction pattern.

Referring to FIG. 1, in one embodiment, the solid Form E ischaracterized by an XRPD Pattern having the following peaks:

Relative 2-Theta Intensity (%) 7.07 >30% 8.24 >30% 14.29 >30% 23.83 >30%24.82 >30%

In another embodiment, the solid Form E is characterized by an XRPDPattern having the following peaks:

Relative 2-Theta Intensity (%) 7.07 >10% 8.24 >10% 12.26 >10% 13.87 >10%14.29 >10% 14.96 >10% 16.33 >10% 18.38 >10% 18.96 >10% 19.93 >10%23.83 >10% 24.82 >10% 25.33 >10% 25.79 >10% 28.17 >10% 28.88 >10%29.62 >10% 32.32 >10% 36.68 >10% 38.41 >10%

The present invention also provides a solid form of(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicacid (4a) designated as Form B. In some embodiments, the solid Form B ischaracterized by one or more peaks corresponding to 2-theta valuesmeasured in degrees of 9.2±0.2, 18.1±0.2, 19.1±0.2, and 32.0±0.2 in anX-ray powder diffraction pattern. In other embodiments, solid Form B isfurther characterized by one or more peaks corresponding to 2-thetavalues measured in degrees of 21.4±0.2, 30.1±0.2, 29.9±0.2, and 26.1±0.2in an X-ray powder diffraction pattern.

Referring to FIG. 2, in one embodiment, the solid Form B ischaracterized by an XRPD Pattern having the following peaks:

Relative 2-Theta Intensity (%) 6.40 >30% 9.12 >30% 18.07 >30% 19.09 >30%21.42 >30%

In another embodiment, the solid Form B is characterized by an XRPDPattern having the following peaks:

Relative 2-Theta Intensity (%) 6.40 >10% 9.19 >10% 18.07 >10% 18.81 >10%19.09 >10% 21.43 >10% 24.88 >10% 25.32 >10% 25.75 >10% 26.06 >10%28.15 >10% 29.87 >10% 30.06 >10% 31.92 >10% 32.02 >10%

In another embodiment, the solid Form B has the solid state ¹H NMRspectrum presented in FIG. 3.

Referring to FIG. 4, in another embodiment, the solid Form B ischaracterized by a dehydration temperature of about 73° C. In otherexamples, solid Form B is characterized by an onset temperature of about40° C. And, in some examples, solid Form B is characterized by adehydration heat of about 725 J/g. In another embodiment, solid Form Bis characterized by a dehydration temperature of about 137° C. In otherexamples, solid Form B is characterized by an onset temperature of about166° C. And, in some examples, solid Form B is characterized bydehydration heat of 42.0 J/g.

Referring to FIG. 5, in another embodiment, the solid Form B undergoes a25.6% weight loss from ambient temperature to 99.4° C. And, in someembodiments, the solid Form B undergoes a 2.6% weight loss from 99.4° C.to 157.7° C.

The present invention also provides a solid form of(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(Ia) designated as Form A. In some embodiments, solid Form A ischaracterized by one or more peaks corresponding to 2-theta valuesmeasured in degrees of 23.7±0.2, 11.3±0.2, 19.3±0.2, and 15.4±0.2 in anX-ray powder diffraction pattern. In other embodiments, solid Form A isfurther characterized by one or more peaks corresponding to 2-thetavalues measured in degrees of 28.9±0.2 and 21.5±0.2 in an X-ray powderdiffraction pattern.

Referring to FIG. 6, in one embodiment, the solid Form A ischaracterized by an XRPD Pattern having the following peaks:

Relative 2-Theta Intensity (%) 11.35 >30% 15.39 >30% 19.26 >30%21.47 >30% 23.69 >30% 28.88 >30%

In another embodiment, the solid Form A is characterized by an XRPDPattern having the following peaks:

Relative 2-Theta Intensity (%) 11.3492 >10% 11.78 >10% 13.95 >10%15.39 >10% 19.26 >10% 21.47 >10% 23.69 >10% 24.53 >10% 28.88 >10%29.86 >10% 34.83 >10%

Referring to FIG. 7, in another embodiment, the solid Form A ischaracterized by a melting point of about 262° C. In other examples,solid Form A is characterized by onset temperature of about 260.8° C.And, in some examples, solid Form A is characterized by melting heat ofabout 140.5 J/g.

The following preparative examples are set forth in order that thisinvention is more fully understood. These examples are for the purposeof illustration only and are not to be construed as limiting the scopeof the invention in any way.

Analytical Methods Used:

(A) HPLC on C18 column. Mobile phase was acetonitrile/water/TFA(60:40:0.1). Flow rate was 1.0 mL/min. Detection at wavelength of 230nm. Run time was 25-26 minutes.

(B) HPLC on C18 column. Mobile phase was acetonitrile/water/TFA(90:10:0.1). Flow rate was 1.0 mL/min. Detection at wavelength of 230nm.

(C) HPLC on a Waters XBridge Phenyl column, 4.6×150 mm, 3.5 μm. Mobilephase A was water/1M ammonium formate, pH 4.0 (99:1). Mobile phase B wasacetonitrile/water/1M ammonium formate, pH 4.0 (90:9:1). Gradient 5% to90% B in 15 minutes. Total run time 22 minutes. Flow rate 1.5 mL/min.Detection at UV, 245 nm.

T=25° C.

(D) HPLC on a Waters XBridge Phenyl column, 4.6×150 mm, 3.5 μm. Mobilephase A was water/1M ammonium formate, pH 4.0 (99:1). Mobile phase B wasacetonitrile/water/1M ammonium formate, pH 4.0 (90:9:1). Gradient 15% to90% B in 15 minutes. Total run time 22 minutes. Flow rate 1.5 mL/min.Detection at UV, 220 nm. T=35° C.

(E) XRPD Analysis: The XRPD patterns were acquired with either a BrukerD8 Discover or Bruker D8 Advance diffractometer.

Bruker D8 Advance System: The XRPD patterns were recorded at roomtemperature in reflection mode using a Bruker D8 Advance diffractometerequipped with a sealed tube Cu source and a Vantec PSD detector (BrukerAXS, Madison, Wis.). The X-ray generator was operating at a voltage of40 kV and a current of 40 mA. The powder sample was placed in a siliconor PMM holder. The data were recorded in a q-q scanning mode over therange of 4°-45° 2q with a step size of 0.014° and a dwell time of 1 sper step.

Bruker D8 Discover System: The XRPD patterns were acquired at roomtemperature in reflection mode using a Bruker D8 Discover diffractometerequipped with a sealed tube source and a Hi-Star area detector (BrukerAXS, Madison, Wis.). The X-Ray generator was operating at a voltage of40 kV and a current of 35 mA. The powder sample was placed in a nickelholder. Two frames were registered with an exposure time of 120 s each.The data frames were subsequently integrated over the range of4.5°-22.4° and 21.0°-39.0° 2q merged into one continuous pattern.

(F) Thermogravimetric Analysis (TGA): TGA was conducted on a TAInstruments model Q5000 thermogravimetric analyzer. Approximately 1-4 mgof solid sample was placed in a platinum sample pan and heated in a 90mL/min nitrogen stream at 10° C./min to 300° C. All thermograms wereanalyzed using TA Instruments Universal Analysis 2000 software V4.4A.

(G) Differential Scanning Calorimetry (DSC): DSC was conducted on a TAInstruments model Q2000 calorimetric analyzer. Approximately 1-4 mg ofsolid sample was placed in a crimped aluminum pinhole pan and heated ina 50 mL/min nitrogen stream at 10° C./min to 300° C. All data wereanalyzed using TA Instruments Universal Analysis 2000 software V4.4A.

(H) SSNMR Experimental: Solid state NMR spectra were acquired on theBruker-Biospin 400 MHz Advance III wide-bore spectrometer equipped withBruker-Biospin 4 mm HFX probe. Samples were packed into 4 mm ZrO₂ rotors(approximately 70 mg or less, depending on sample availability). Magicangle spinning (MAS) speed of typically 12.5 kHz was applied. Thetemperature of the probe head was set to 275K to minimize the effect offrictional heating during spinning. The proton relaxation time wasmeasured using ¹H MAS T₁ saturation recovery relaxation experiment inorder to set up proper recycle delay of the ¹³C cross-polarization (CP)MAS experiment. The recycle delay of ¹³C CPMAS experiment was adjustedto be at least 1.2 times longer than the measured 1H T₁ relaxation timein order to maximize the carbon spectrum signal-to-noise ratio. The CPcontact time of ¹³C CPMAS experiment was set to 2 ms. A CP proton pulsewith linear ramp (from 50% to 100%) was employed. The Hartmann-Hahnmatch was optimized on external reference sample (glycine). SPINAL 64decoupling was used with the field strength of approximately 100 kHz.The chemical shift was referenced against external standard ofadamantane with its upfield resonance set to 29.5 ppm.

The following preparative examples are set forth in order that thisinvention is more fully understood. These examples are for the purposeof illustration only and are not to be construed as limiting the scopeof the invention in any way.

Example 13-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a) Example 1a 3-bromo-1H-pyrrolo[2,3-b]pyridine (6a)

7-azaindole (5a) (6.9 kg, 58.4 moles) was added to a 200 L glass-linedreactor containing 52.6 kg DMF. A solution of Br₂ in DMF (9.7 kg Br₂ in14.7 kg DMF) was added drop wise to maintain the mixture temperature ofabout 0-10° C. After the addition was complete, the temperature wasmaintained at about 0-10° C. The completeness of the reaction wasmeasured by HPLC (method A) with sample aliquots after 30 minutes. Thereaction was considered complete when the 7-azaindole was less than 3%(after about 2 hours and 40 minutes).

The reaction was quenched with 10% aqueous solution of NaHSO₃ (17.5 kg)while maintaining the temperature below 15° C. A saturated aqueoussolution of NaHCO₃ (61.6 kg) below 25° C. was added to adjust the pH toabout 7 to 8. After neutralization, the mixture was transferred into a50 L vacuum filter and filtered. The resultant cake was washed withwater (18 kg) and then petroleum ether (12 kg). The cake was dried in atray dryer at about 50-60° C. until the water content detected by KF(Karl Fisher reaction) was less than 0.8%. A yellow solid resulted (10.3kg, 99.1% purity as measured by HPLC (method A), 89.6% yield of3-bromo-1H-pyrrolo[2,3-b]pyridine (6a)).

Example 1b 3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7a)

3-bromo-1H-pyrrolo[2,3-b]pyridine (6a) (10.7 kg, 54.3 moles) was addedto 94.3 kg of THF in a 200 L glass-lined reactor. The solid wasdissolved completely by stirring. After the mixture was cooled to about10-15° C., NaH (3.4 kg, 85 moles) was added in portions (about 200-250 geach portion) every 3 to 5 minutes while venting any H₂ gas released bythe reaction. After the addition of NaH, the mixture was stirred for onehour while maintaining the temperature of about 10-20° C.4-methylbenzenesulfonylchloride (12.4 kg, 65.0 moles) was added at arate of 0.5 kg/10 minutes at about 10-20° C. After the addition wascomplete, the temperature was maintained at about 10-20° C. Thecompleteness of the reaction was measured by HPLC (method A) with samplealiquots after 30 minutes. The reaction was considered complete when thepeak area of 3-bromo-1H-pyrrolo[2,3-b]pyridine (6a) was less than 1%(after about 1.5 hours).

The reaction was quenched with water (10.7 kg) while maintaining thetemperature below 20° C. Dichloromethane (41.3 kg) was added to themixture. Then 3% HCl (42.8 kg) was added into the mixture whilemaintaining the temperature below 25° C. After the addition, the phaseswere allowed to separate for 0.5 hour. The aqueous phase was extractedtwice with dichloromethane. During each extraction, the mixture wasstirred for 15 minutes and then held for 15 minutes. All the organicphases were combined. The combined organic phases were washed with 3%HCl (33.4 kg) and water (40 kg). During each wash, the mixture wasstirred for 15 minutes and then held for 30 minutes.

The mixture was transferred into a 50 L vacuum filter and filteredthrough silica gel (3 kg). The cake was washed with dichloromethane (35kg) twice. The filtrate and washings were combined. The organic phasewas concentrated below 40° C. under vacuum of a pressure less than−0.085 MPa until 10 L mixture remained. Petroleum ether (9 kg) was addedinto the residue. The mixture was stirred until it was homogeneous. Theslurry was transferred into a 50 L vacuum filter and filtered. The cakewas washed with petroleum ether (9 kg). A light brown solid resulted (17kg, 99.7% purity as measured by HPLC analysis (method A), 94% yield of3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7a)).

Example 1c 1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8a)

THF (28.5 kg) and 3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7a) (4 kg)were added to a 72 L flask. The mixture was stirred until the soliddissolved completely. Triisopropyl borate (3.2 kg) was added and themixture was cooled to below −80° C. n-BuLi (4.65 kg) was added drop wiseat a rate of about 0.6-0.9 kg/hour maintaining the temperature of about−80 to −90° C. After the addition, the temperature was maintained at −80to −90° C. The completeness of the reaction was measured by HPLC (methodA) with sample aliquots after 30 minutes. The reaction was consideredcomplete when the peak area of 3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine(7a) was less than 4%.

Water (2 kg) was slowly added to the mixture to quench the reaction. Themixture temperature returned to about 15-25° C. The mixture wastransferred to a 50 L reactor to be concentrated below 40° C. undervacuum of a pressure less than −0.08 MPa until no THF distilled out. Theresidue was dissolved into water (25 kg) and 10% aqueous NaOH solution(26 kg). The mixture was stirred until the solid dissolved completely.The mixture was transferred into a vacuum filter and filtered. Thefiltrate was extracted twice with MTBE (21 kg each) at about 20-30° C.During each extraction, the mixture was stirred 15 minutes and held 15minutes. HCl (28 L) was added into the aqueous phase to adjust the pH tobetween 3 and 4 while maintaining the temperature of about 10-20° C. Themixture was stirred at about 10-15° C. for 1 hour. The mixture wastransferred into a centrifuge and filtered. The resultant cake afterfiltering was washed with water (5 kg) and petroleum ether (5 kg). Thecake was dried at 35-45° C. until the LOD (loss on drying) was less than3%. An off-white solid resulted (2.5 kg and 98.8% purity as measured byHPLC analysis (method A), 69.4% yield of1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8a)).

Example 1d3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a)

Dichloromethane (165.6 kg) and pinacolate alcohol (3.54 kg) were addedto a 200 L glass-lined reactor. The mixture was stirred until the soliddissolved completely. Then, 1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronicacid (8a) (8.65 kg) was added in portions (2 kg every 5 minutes) whilemaintaining the temperature of about 20-30° C. After the addition, thetemperature was maintained at about 20-30° C. while stirring. Thecompleteness of the reaction was measured by HPLC (method B) with samplealiquots every 60 minutes. The reaction was considered complete when thepeak area of 1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8a) wasless than 1%.

The mixture was filtered through silica gel (3 kg). The cake was rinsedtwice with dichloromethane (15 kg each rinse). The filtrate was combinedwith the washing liquids, and then concentrated below 30° C. undervacuum at a pressure less than −0.08 MPa until no fraction distilledout. Solvent was continued to be removed by vacuum for 2 hours.Isopropanol (17.2 kg) was added to the residue. The mixture was heatedto reflux at about 80-85° C. The mixture refluxed for 30 minutes untilthe solid dissolved completely. The mixture was cooled below 35° C., andthen to about 0-10° C. The mixture crystallized at 0-10° C. for 2 hoursand was then filtered. After filtration, the resultant cake was dried atabout 35-45° C. until the water content detected by KF (Karl Fisherreaction) was less than 0.5% and the LOD (loss on drying) was less than0.5%. An off-white solid resulted (8.8 kg and 99.7% purity as measuredby HPLC analysis (method B) of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a)).

Example 2a Preparation of(R)-2-methyl-2-(2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)butanoicacid (3a)

Tripotassium phosphate (K₃PO₄) (7.20 kg, 3 equiv.) was mixed with threevolumes of water (9.0 kg). The mixture was agitated for at least 20minutes, cooled to a temperature of ≦30° C. and added to acetonitrile(16.8 g, 7 volumes) into a 120 L reactor. The resultant mixture wasagitated. 3.0 kg (11.3 moles, 1.0 equiv.) of(R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid hydrochloride(2a) were added to the reaction mixture in the reactor while maintaininga temperature ≦30° C. The mixture was agitated for at least 20 minutes.5.16 kg (13.0 moles, 1.15 equiv.) of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a) were then added to the reactor. The reaction mixture was agitatedand de-gassed with N₂ sparging for at least 30 minutes. The mixture washeated to 65±5° C.

In a separate vessel, 0.075 kg (0.03 equiv.) of palladium(II) acetatewas mixed with 4.80 kg (2 volumes) of de-gassed acetonitrile (CH₃CN).This mixture was agitated until homogenous. 0.267 kg (1.02 moles, 0.09equiv.) of triphenylphosphine (PPh₃) was added and the resultant mixturewas agitated for at least 30 minutes at 20±5° C. The palladium(II)acetate/PPh₃/CH₃CN mixture was then added to the reactor above whilemaintaining the nitrogen purge. The reactor contents were heated to75±5° C. for at least 17 hours under nitrogen purge. After 5 hours theconversion was shown to be about 86% complete as measured by HPLCanalysis (method C) of a 1.0 mL aliquot. Additional catalyst andcompound of Formula Ia (900 g, 2.26 moles, 0.2 equiv.) were then addedto the reaction mixture and the mixture was stirred. After an additional12 hours, the reaction was shown to be 99.7% complete as measured byHPLC analysis (method C) of a 1.0 mL aliquot. The additional catalystadded above was prepared by dissolving 37.5 g palladium(II) acetate in 1volume of acetonitrile (which was de-gassed for 20 minutes), and thenadding 133.5 g of triphenylphosphine.

Example 2b(R)-2-methyl-2-(2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)butanoicacid (3a)

To (R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acidhydrochloride (2a) (limiting reagent) and3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1.15 eq) add 2-propanol (0.6 vol) and begin degassing with nitrogen.Add 6N aqueous NaOH (3.2 eq) and continue degassing. ChargePdCl₂(Amphos)₂ (0.0014 eq) as a slurry in 2-propanol (0.06 vol).Continue the degassing for at least 30 minutes then warm the mixture toa temperature of between 70-75° C. to generate the compound of Formula(3a). The reaction is deemed complete when HPLC analysis shows <1.0% of(R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid hydrochloride(2a) remaining.

Example 3a(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicacid (4a)

A solution of 4N aqueous KOH, which was previously prepared with 6.0 kgof KOH in 27.0 kg of water at a rate to control the temperature rise,was added to the reactor above and the reaction was heated to 75±5° C.for at least 5 hours while agitating the mixture. An aliquot of about1.0 mL was removed from the reaction mixture and analyzed by HPLC(method C) to show 98.6% compound of Formula 4a and 1.4% compound ofFormula 3a.

15.0 kg (5 volumes) of water was added to the reactor. The reactionmixture was cooled to 35±5° C. Isopropyl acetate (7.8 g, 3 volumes) wasadded, and the reaction mixture was agitated for at least 5 minutes. Thereaction mixture was filtered through a 4-cm pad of celite in an 18-inchNutsche filter. The reactor was rinsed with 9.0 kg of water and thewater was then used to rinse the celite pad. The aqueous and organicphases were separated. 0.9 kg of Darco G-60 activated carbon (30% w/w)was added to the aqueous phase in a 120-liter reactor. The pH of themixture was adjusted to less than 1.0 with concentrated HCl solution at25±10° C. and held for at least 4 hours. If necessary, the pH wasreadjusted with 6N NaOH. The mixture was then filtered through a Nutshcefilter, which was equipped with a filter cloth, and the solids wererinsed with 6.0 kg (2 volumes) of 1N HCl. The filter cake was maintainedunder positive pressure of nitrogen for at least 30 minutes. The HClfiltrate was agitated and heated to 25±5° C. 0.9 kg of Darco G-60activated carbon was added to the HCl filtrate and the mixture wasstirred for at least 4 hours. The mixture was then filtered through aNutshce filter, which was equipped with a filter cloth, and the solidswere washed with 6.0 kg (2 volumes) of 1N HCl. The second filter cakewas maintained under positive pressure of nitrogen for at least 30minutes.

The HCl filtrate was again agitated and heated, charcoal was added andfiltering step was repeated with a Nutshce filter, which was equippedwith a 0.45 μm in-line filter between the Nutsche filter and thereceiver flask, to yield a third filter cake and a final filtrate. Thesolids were washed with 6.0 kg of 1N HCl. The third filter cake wasmaintained under positive pressure of nitrogen for at least 30 minutes.

The pH of the final filtrate was adjusted to between 4.5 and 5.0 using6N NaOH while the temperature was maintained between 25±5° C. Ifnecessary, the pH was readjusted using 1N HCl. The final filtrate wasthen cooled to 5±5° C. and agitated for at least 2 hours. The mixturewas filtered was filtered with a Nutshce filter, which was equipped witha filter cloth. The solids were rinsed with 6.0 kg (2 volumes) of water.The final filter cake was maintained under positive pressure of nitrogenfor at least 30 minutes.

The wet solids (i.e., filter cakes) were dried in a drying oven at ≦60°C. under vacuum, with a nitrogen purge, over 5 days to yield 3.561 kg of(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicacid (4a).

The(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicacid (4a) generated above is designated as Forms B and E. These solidforms were subject to XRPD, solid state 1H NMR, and TSG analysesdescribed under (E) and (F), above. The results from these analyses arepresented in FIGS. 1-4.

Example 3b(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicacid (4a)

To the reaction mixture in Example 2b, charge a solution of KOH (8.8 eq)in water (7.3 vol) and agitate the batch at a temperature of from 70-75°C. until HPLC analysis shows conversion from the intermediate to(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicacid (4a) reaches >99%. Cool the batch to 20-25° C. then charge DarcoG-60 activated carbon (30 wt % based on the compound of Formula (2a))and agitate the batch for 12-24 hrs at 20-25° C. Filter the slurry,rinsing the solids with water (2×1 vol). Cool the batch to 15-20° C.then adjust the pH of the batch to <5 with conc. HCl while maintaining abatch temperature no more than 20-25° C. Perform fine adjustment of pHback to 5.5-6 (target pH 6) via 6M NaOH. Adjust the batch temperature to20-25° C. then seed with the compound of Formula (2a) (0.4 wt % dryseed). Stir the slurry for no less than 2 hrs. Charge water (12 vol)over 8 hrs then stir the slurry for no less than 4 hrs. Filter the batchand rinse the cake with water (2×2 vol) then n-heptane (2 vol). Dry thesolids at 80° C. to give(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicacid (4a).

Example 3c(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicacid (4a)

To the reaction mixture in Example 2b, charge a solution of KOH (8.8 eq)in water (7.3 vol) and agitate the batch at a temperature of from 70-75°C. until HPLC analysis shows conversion from the intermediate to(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicacid (4a) reaches >99%. Cool the batch to 15-25° C. and adjust the pH to<5 with conc. HCl. Perform a fine adjustment of the pH to 5.5-6 using 6MNaOH. Adjust the batch temperature to 20-25° C., and seed the seed withthe compound of Formula (2a) (0.4 wt % dry seed). Stir the slurry fornot less than 2 hrs. Charge water (12 vol) over 8 hrs then stir theslurry for not less than 4 hrs. Filter the batch and rinse the cake withwater (2×2 vol) then n-heptane (2 vol). Dry the solids at 80° C. to give(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicacid (4a).

Example 4a Preparation of(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(Ia)

Diisopropylethylamine (DIEA) (3.61 kg, 28.1 moles, 2.5 equiv.) was addedto(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicacid (4a) (3.5 kg, 11.24 moles, 1.0 equiv.) in 7 volumes (32.6 kg) ofdichloromethane (CH₂Cl₂ or DCM) while keeping the temperature at ≦30° C.Water (0.103 kg) was added to make 5.5±0.5% total water content for thereaction system, and the mixture was stirred at ≦30° C. for at least 30minutes. The reaction mixture was cooled to 0±5° C. Propylphosphonicanhydride solution (17.9 kg, 28.1 moles, 2.5 equiv.) was added to themixture while maintaining the temperature below 20° C. The mixture wasagitated for at least an hour keeping the temperature at 20±5° C., then2,2,2-trifluoroethylamine (1.68 kg, 16.86 moles, 1.5 equiv.) was addedwhile maintaining the temperature below 20° C. The reaction mixture waswarmed to 25±5° C. and agitated for 5 hours while holding thetemperature. A 1.0 mL aliquot was removed and the reaction wasdetermined to be 100% complete. Water (17.5 kg, 5 volumes) was added tothe reaction mixture, and the resultant mixture was agitated for atleast 30 minutes while maintaining the temperature below 30° C.

The mixture was concentrated under vacuum with a rotary evaporator at atemperature ≦45° C. Isopropylacetate (1.55 kg, 0.5 volumes) was added tothe concentrated aqueous solution, and the pH of the solution wasadjusted to 7.5-8.0 using 6N NaOH solution at ≦35° C. The mixture wascooled to 10±5° C. and stirred at for at least one hour. If necessary,6N HCl was added to readjust the pH of mixture to 7.5-8.0. The resultantslurry was filtered and washed with water (10.5 kg, 3 volumes). Thefilter cake was maintained under positive pressure of nitrogen for atleast 30 minutes. The wet cake was dissolved in methanol (44.7 kg, 12volumes) by agitation, and the solution was treated with PL-BnSHMP—Resin (BNSHMP) polymer resin (0.235 kg of 5% wt of resin) at 25±5° C.After agitating at 25±5° C. for at least 12 hours, the mixture wasfiltered. The solids were washed with methanol (2.77 kg, 1 volume). Thefiltrate was concentrated under vacuum in a rotary evaporator at atemperature ≦50° C. The filtrate was not concentrated to dryness. Theconcentrated filtrate was allowed to sit at room temperature for about2.5 days. The mixture was then stirred until homogeneous and heated to40° C., followed by slow addition of pre-heated water (56.1 kg at 45°C.) while maintaining a temperature of 45±5° C. After the mixture wasspun for 1 hour, the remaining methanol was concentrated further, butnot concentrated to dryness. The resultant mixture was cooled down to atleast 5±5° C. and agitated for at least 2 hours. The product wasfiltered, and the solids were washed with water (10.5 kg, 3 volumes).The filter cake was maintained under positive pressure of nitrogen forat least 30 minutes. The isolated product was dried to a constant weightunder vacuum in a drying oven at a temperature of ≦70° C. with anitrogen purge to yield(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(Ia) (4.182 kg, white powder, 0.18% water content, 98.6% AUC using HPLC(method D)).

The solid state(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(Ia) generated above, is designated as Form A. This compound was subjectto XRPD, TGS, and DSC analyses described under (E) and (F), above. Theresults from these analyses are presented in FIGS. 5-7.

Example 4b Preparation of(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(Ia)

To(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicacid (4a) (limiting reagent) charge 2-methylTHF (7.5 vol), then chargeT₃P® (2.0 eq, 50% w/w in 2-MeTHF). Heat the mixture to 60-65° C. andmaintain this temperature for no less than 3 hrs and the solids arecompletely dissolved. Cool to 20-25° C. then charge2,2,2-trifluoroethylamine (2.0 eq). Continue agitation for no less than6 hrs at 20-25° C. and until HPLC analysis showed <1.0% of(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicacid (4a). Slowly charge a Na₂CO₃ solution (15 vol, 1.165M) whilemaintaining a batch temperature <30° C. Stir the mixture for 30 min thenseparate the phases. Wash the organic phase with water (4 vol).Emulsions have been observed at this point and can be addressed throughaddition of NaCl solution. Charge methanol (7 vol) then distill to 4vol. Repeat 3 times. Prior to crystallization, adjust the total volumeto approximately 11 vol. Heat the mixture to 50-55° C. then add water(2.45 vol, final solvent composition 22% water in methanol) over 30 min.Seed the batch with(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(Ia) (1 wt % seed based on the compound of Formula (4a)). Stir for 4 hrsat 50-55° C. then add water over 24 h until the mixture is approximately58 wt % water in methanol. Cool to 20-25° C., stir 1 h, then filter.Wash the cake with water (2 vol). Dry the solids at 60-65° C. to give(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(Ia).

Example 5 Preparation of(R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid hydrochloride(2a)

To a solution of K₂CO₃ (2 eq.) in water (3 vol) was addedD-isovaline*HCl (1.0 eq.). The resulting solution was stirred for 20min. then 2,4-dichloropyrimidine (1.1 eq.) and IPA (7 vol) were added tothe reaction mixture consecutively. The resulting mixture was heated toreflux (˜82° C.). After checking completion of the reaction by HPLCanalysis (NMT 3.0% (AUC) of 2,4-dichloropyrimidine, ca. 5-6 h), thesolution was concentrated to 4 vol. Water (4 vol) and IPAC (4 vol) wereadded and the mixture was stirred and acidified to pH=1.2-1.4 using 6NHCl aqueous solution. After stirring no less than 20 min, the layerswere separated. IPAC (6 vol) was added to the aqueous layer and the pHof the mixture was adjusted to 3.0-3.5 with 50% aqueous NaOH. Afterstirring no less than 20 min., the layers were separated. The aqueouslayer was extracted with IPAC (3 vol). The combined IPAC layers weredried (Na₂SO₄) and filtered. IPA (1 vol) was added to the filtrate. 5-6NHCl/IPA (0.85 eq.) was added dropwise. The mixture was seeded with(R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid hydrochloride(0.01 wt. eq.) to crystallize the product with vigorous stirring. Afterstirring no less than 4 h, the product was collected by filtration,washed (4:1 IPAC/IPA, 2×1.2 vol), and dried in a vacuum oven at 50° C.with a N₂ bleed to constant weight to afford(R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid hydrochloride(2a) as an off-white solid.

Example 6 Preparation of(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoicacid (4a)

(R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a) (10.00 g,37.58 mmol) and3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a) (17.21 g, 43.22 mmol) were charged into a 250 mL reactor and purgedwith nitrogen gas. Under nitrogen gas degassing and stirring, 52.00 mLof IPA was charged into the reactor followed by 6M NaOH (20.05 mL).After degassing the stirring mixture for 15 min,4-ditert-butylphosphanyl-N,N-dimethyl-aniline palladium(II)dichloride(37.25 mg, 0.05261 mmol) was charged into the reactor as a slurry with2.00 mL of IPA. The resulting mixture was further degassed for another20 min. Under positive nitrogen pressure, the reaction mixture washeated to 74° C. until the HPLC samples confirmed that the reaction wascomplete. Once the reaction was complete, 6M NaOH (6.263 mL) was chargedinto the reactor as a solution in water (74.00 mL) and the reaction wasmaintained at 74° C. until HPLC showed complete de-tosylation of theproduct.

The reaction mixture was cooled to 25° C. and adjusted to have a pH of0.4-0.6 using 11M HCl (3.146 mL). Activated charcoal (0.3 g, 30 wt %)was charged into the reactor, and the resulting mixture was stirredfor >12 Hr. The reaction mixture was filtered to remove the charcoal,and water (50 mL) was added to the filtrate after returning it to thecleaned reactor. The pH of the reaction mixture was adjusted to 5.5-6.0using 6M NaOH (6.263 mL). The reaction mixture was heated to 64° C.under stirring. The reaction mixture was maintained under stirring at64° C. for a period of 60 min. after the formation of a solution. Thereactor was cooled at a rate of 20° C./hr until reaching a temperatureof 25° C. The reaction mixture was continuously stirred at 25° C. for atleast 4 hr. The batch was then filtered and washed with water (10 mL)followed by heptane (20 mL). The solids were collected at dried undervacuum at 60° C.

Example 7 Preparation of Deuterated(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(Ia-D)

To a mixture of(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(Ia) (85 mg, 0.2166 mmol) in D₂O (20 ml) was added 10% Pd/C (15 mg). Theresulting mixture was hydrogenated via balloon at reflux in a 160° C.bath for 20 hours. After 20 hours, the mixture was cooled andconcentrated to ⅓ volume. Another 20 ml D₂O was added to the mixture andrefluxed under a balloon of H₂. The mixture was cool filter washed withMeOH and ETOAc, and concentrated to dryness, generating an off whitesolid. CMS shows D incorporation but probably not in the alkyl sidechains. NMR shows partial addition of D₂ at 5 aromatic sites.

This off white solid was taken up in D₂O (20 ml) was added fresh 10%Pd/C (15 mg) and placed on a hydrogenation apparatus. The reaction wasevacuated and pressurized with H₂ up to 40 psi 3× times over 10 min. Thepressure was released and the flask was swept with H₂ as the flask wasreclosed. This sealed flask was then put in a 160° C. bath behind ablast shield and heated at 160° C. for 16 hours.

The reaction mixture was cooled and diluted with ETOAC, washed withwater, brine dry over sodium sulfate filter and concentrated. Theproduct was purified by flash chromatography with the following mobilephase: 0 MDC to 10% MeOH/MDC.

hu 1H-NMR showed that most ¹H atoms on the aromatic rings were replacedwith deuterium atoms.

Example 8 Preparation of [¹³C,¹⁵N]-enriched(R)-2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(Ia*)

205 mg (1.73 mmol) of [¹³C,¹⁵N]-enriched uracil was mixed with 5 mlPOCl₃ and 2 drops of PhNEt₂ and heated to 100° C. for about 12 hrs. Thesolvent was evaporated, ethyl acetate was added, and the resultingmixture was stirred for 2 hrs, transferred, and the solvent wasevaporated to generate [¹³C,¹⁵N]-enriched 2,4-dichloropyrimidine (11a*)(260 mg of white solid).

The [¹³C,¹⁵N]-enriched 2,4-dichloropyrimidine (260 mg) was mixed with2-amino-2-methyl-N-(2,2,2-trifluoroethyl)propanamide (267 mg, 0.8 eq)and DIEA (1.47 mL) in 2 mL of isopropyl alcohol. The mixture was heatedto 100° C. for about 11 hours, the solvent was evaporated and ethylacetate was added to the reaction mixture. The reaction mixture wasfurther washed with 1N HCl and brine and dried on Na₂SO₄ to generate 58mg of [¹³C,¹⁵N]-enriched(R)-2-((2-chloropyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(iiic). ES⁺=317.1, ES⁻=315.2.

[¹³C,¹⁵N]-enriched(R)-2-((2-chloropyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(iiic) (58 mg) is mixed with3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a) (80 mg), 2N Na₂CO₃ (275 L), DME (2 mL), and Pd(PPh₃)₄ (10 mg). Thereaction mixture is stirred at 90° C. for about 12 hr. The solvent wasevaporated and ethyl acetate was added to the reaction mixture. Thereaction mixture was then filtered over SiO₂ and eluted with ethylacetate to generate 126 mg of crude [¹³C,¹⁵N]-enriched(R)-2-methyl-2-((2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)butanamide(iiid). ES⁺=553.2, ES⁻=551.5.

120 mg of [¹³C,¹⁵N]-enriched(R)-2-methyl-2-((2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)butanamide(iiid) was treated with LiOH (800 μL, 1N) in 2 mL of THF. The reactionmixture was heated to 80° C. for about 10 hrs, and the solvent wasevaporated. The reaction mixture was extracted with ethyl acetate,filtered over SiO₂, and eluted with ethyl acetate to generate 19.3 mg of[¹³C,¹⁵N]-enriched(R)-2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(Ia*). ES⁺=399.1, ES⁻=397.6.

Example 9 Preparation of [¹⁴C]-enriched(R)-2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(Ia**)

Propiolic acid (0.393 g, 5.63 mmol) was added dropwise to a suspensionof [¹⁴C]-enriched urea (200 mCi, 55 mCi/mmol, 218.57 mg, 3.52 mmol) inpolyphosphoric acid (4.3 g) and this suspension was heated at 85° C. for8 hours. It was diluted with water (11 mL) at 0° C. then neutralizedwith NH₄OH (aq, 28-30%) in an ice-water bath. The residue was dissolvedand suspended with NH₄OH (aq, 28-30%, 43 mL) and methanol (43 mL). Theresulting solids were removed by filtration, and the filtrate wasevaporated. A silica gel column chromatography (MeOH(10):DCM(90) toMeOH(20):DCM(80)) provided a crude compound (85% radiochemical purity,142.2 mCi. 142.2×0.85=120.9 mCi).

To a solution of triethylamine (10 g, 98.8 mmol) in ethyl acetate (100mL) was added 1N HCl etherate (119 mL, 119 mmol) at 0° C. The resultingsuspension was stirred for 3 hours at 0° C. to water bath temperatureunder argon. The white suspension was filtered and the obtained solidwas washed with ethyl acetate (80 mL). The solid was dried under vacuumovernight.

A mixture of [¹⁴C]-enriched uracil (crude 142 mCi, 2.73 mmol) andEt₃NHCl (75 mg, 0.546 mmol) in POCl₃ (0.75 mL, 8.19 mmol) was heatedslowly at 130-140° C. in an oil bath for 2 hours. The resulting reactionmixture was cooled to 50-60° C. then added PCl₅ (1.14 g, 5.46 mmol) andPOCl₃ (0.6 mL, 6.56 mmol) then stirred additional 1 hour at 50-60° C.The POCl₃ was removed by rotavap at 45° C. Silica gel columnchromatography (ethyl acetate:hexanes (1:9) to ethyl acetate hexanes(3:7)) provided 0.261 g (90 mCi) of [¹⁴C]-2,4-DCP with 99.9%radiochemical purity by instant imager.

To a solution of K₂CO₃ (526.2 mg, 3.80 mmol) in water (1.6 mL, 6 volume)was added isovaline-HCl (292.4 mg, 1.90 mmol). The resulting solutionwas stirred for 10 minutes. A solution of [¹⁴C]-enriched2,4-dichloropyrimidine (11a**) (0.261 g, 90 mCi) in isopropanol (5.2 mL,20 volume) was added dropwise at room temperature, and the resultingmixture was heated at 85-90° C. for 18 hours. The mixture was thenconcentrated to 4 volumes, then 1N NaOH (6 mL) and isopropyl aceate (6mL) were added. The aqueous phase was separated and the organic phasewas extracted with 1N NaOH (6 mL×2). The combined aqueous layer wasacidified to pH=3.0-3.5 using 6N HCl (aq). The resulting solution wasextracted with isopropyl acetate (15 mL×3). The collected organic layerwas concentrated to 3-4 volumes, then 1N HCl etherate (1.73 mL, 1.73mmol) was added drop wise at 0° C. and stirred for 15 minutes. Theorganic solvent was decanted and the solid was washed with isopropylacetate (5 mL×2). The solid was dried under vacuum and obtained 360 mgof (R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a**) with70% radiochemical purity by instant imager to provide(R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a**).

To a solution of K₂CO₃ (0.557 g, 4.02 mmol) and(R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a**) inwater (2.19 mL) was added acetone (4.38 mL), and the resulting mixturewas stirred for 5 minutes. The (0.641 g, 1.61 mmol), PPh₃ (31.6 mg, 0.12mmol) were added then acetone (4.38 mL) was added again. The reactionvessel was purged with nitrogen then Pd(OAc)₂ (9.8 mg, 0.04 mmol) wasadded, all at once. The vessel was charged with nitrogen and the lid wasclosed tightly with sealed reactor. The resulting reaction mixture wasstirred at 75-80° C. oil bath for overnight. A half amount of solventwas removed by nitrogen streaming at oil bath then added 2N NaOH (5.5mL). The lid was closed tightly and the mixture was stirred for 3 hoursat 80° C. The solvent was removed then added 1N NaOH (3 mL) to dissolvethe solids in the reaction mixture. 6N HCl was added until a pH of4.5-5.0 was obtained. The resulting reaction mixture was filtered onSep-pak®vac 20 cc (5 g)-C18 cartridge and washed with acetonitrile(50):water (50). After purification, 0.884 g (58.8 mCi) of[¹⁴C]-enriched(R)-2-methyl-2-(2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)butanoicacid (3a**) was obtained with 85% radiochemical purity as measured byinstant imager.

To a solution of [¹⁴C]-enriched(R)-2-methyl-2-(2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)butanoicacid (3a**) (784 mg, 1.0 mmol, 52.13 mCi) in dichloromethane (16 mL) wasadded N,N-diisopropylethylamine (0.697 mL, 4.0 mmol). The resultingsolution was cooled to 0° C., then T3P (50% wt in ethyl acetate, 0.656mL, 1.1 mmol) was added. After 5 minutes, trifluoroethylamine (0.381 mL,5.0 mmol) was added drop wise. The resulting mixture was stirredovernight at water bath temperature. Water (7 mL), 6N NaOH (8 mL) wereadded and the reaction was stirred for 5 minutes. The organic layer wasseparated and the aqueous layer was extracted with dichloromethane (30mL×3), dried over Na₂SO₄, concentrated, and purified by silica gelcolumn chromatography (MeOH (50) DCM (50) to MeOH (10):DCM(90)). It wasdissolved in methanol (3 mL) and added PL-BnSH MP-Resin (44 mg). Theresulting mixture was agitated for 24 hours at room temperature. It wasfiltered and rinsed the solid with methanol (1 ml) and evaporated thesolvent until dry. The white solid (around 140 mg) was dissolved in 1NHCl (3 mL) and adjusted the pH 7.5-8.0 using 6N NaOH at roomtemperature. The resulting suspension was stirred for 2 hours at 5° C.and obtained the white solid was rinsed with water (0.4 mL×3). Dryingunder vacuum provided 140 mg (19.5 mCi) of [¹⁴C]-enriched(R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide(Ia**).

Example 10a Preparation of Methyl 2-amino-2-methylbutanoate

2-amino-2-methylbutanoic acid HCl salt (20 g, 130.2 mmol) was suspendedin 150 mL methanol. A solution of HCL (4M in dioxane was added and themixture heated to 50° C. overnight. The mixture was cooled to roomtemperature and evaporated to dryness under vacuum. The resultingisovaline methyl ester (20 g) was used without further purification. ¹HNMR (300 MHz, DMSO) δ 3.78-3.64 (m, 1H), 3.61 (s, 3H), 3.54-3.41 (m,1H), 2.50 (d, J=1.6 Hz, 1H), 1.76 (s, 2H), 1.66-1.35 (m, 2H), 1.17 (s,3H), 0.77 (t, J=7.5 Hz, 3H).

Example 10b Preparation of Methyl2-((2-chloropyrimidin-4-yl)amino)-2-methylbutanoate

A 250 mL flask was charged with methyl 2-amino-2-methylbutanoate (8.4 g,54.4 mmol), 2,4-dichloropyrimidine (8.9 g, 59.8 mmol), TEA (5.5 g, 54.4mmol) and 80 mL NMP. The reaction mixture was heated to 80° C. for ˜18hours. After cooling, water (300 mL) was added and the mixture extractedwith MTBE. The organic extracts were washed with water and dried oversodium sulfate. Filtration and evaporation under vacuum afforded 13 g ofan orange oil which was purified by flash chromatography, (0-100% ethylacetate-hexane affording 4.6 g (34%) methyl2-((2-chloropyrimidin-4-yl)amino)-2-methylbutanoate as an oil. ¹H NMR:(CDCl3) δ 8.05-7.88 (m, 1H), 6.28 (δ, 1H), 5.95 (δ, 1H), 4.2-4.0 (g,1H), 3.86 (m, 1H), 2.46 (m, 1H), 2.10 (m, 1H), 2.01 (m, 1H), 1.72 (m,3H), 0.89 (m, 3H). m/e, m+1 244.1

Example 10c Preparation of Methyl2-methyl-2-((2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)butanoate

A 500 mL pressure vessel was charged with 80 mL DME,1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(4.4 g, 11.05 mmol), methyl2-((2-chloropyrimidin-4-yl)amino)-2-methylbutanoate, (2.44 g, 10.05mmol), sodium carbonate (10 mL of 2M aq solution, 20 mmol) and degassedthe mixture with a nitrogen stream for 30 min. Then, Pd(dppf)Cl₂ wasadded, the flask sealed and heated to 90° C. for 15 hours. The mixturewas cooled and filtered through Florisil. Evaporation under vacuum gave7.8 g of a brown residue which was purified by flash chromatography,(0-80% ethyl acetate-hexane affording 3.9 g (81%) methyl2-methyl-2-((2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)butanoate.¹H NMR (CDCl₃) 8.83 (dd, 1H), 8.52 (s, 1H), 8.44 (dd, 1H), 7.28 (dd,4H), 6.27 (d, 1H), 5.29 (s, 1H), 3.74 (d, 3H), 2.38 (s, 3H), 2.34-2.15(m, 1H), 2.18-2.00 (m, 2H), 1.98 (s, 2H), 1.74 (s, 3H), 1.34-1.17 (m,15H), 1.03 (m, 3H). m/e m+1 480.25

Example 10d Preparation of2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methylbutanoicacid

Lithium hydroxide hydrate (1.9 g, 45 mmol) was added to 50 mL THF and 15mL water. Then2-methyl-2-((2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)butanoatewas added and the mixture was heated to reflux for 18 hours. Thereaction was cooled to rt and 50 mL 1M citric acid solution was added.The mixture was extracted with 3×100 mL ethyl acetate where upon a whiteprecipitate formed in the aqueous layer. The product was then filteredfrom the aqueous layer and dried under vacuum affording 1.6 g (68%)2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methylbutanoicacid as white solid. ¹H NMR (300 MHz, MeOD) 8.87 (dd, 1H), 8.32 (m, 2H),7.94 (d, 1H), 3.31 (m, 3H), 2.80 (q, 1H), 2.29-1.95 (m, 2H), 1.68 (s,3H), 0.96 (t, 3H). m/e m+1=312.22.

Example 10e Preparation of2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide

A 100 mL flask was charged with2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methylbutanoicacid (1.6 g, 5.14 mmol), 20 mL DMF, HOBt (243.1 mg, 1.8 mmol), EDC (1.18g, 6.17 mmol) and 2,2,2-trifluoroethanamine (450 L, 5.65 mmol). Stir atrt ˜18 hours. 75 mL water was added and the mixture extracted with 3×100mL MTBE. The combined organics were washed with water, brine and driedover sodium sulfate. The solution was filtered and evaporated undervacuum affording 1.1 g (54%) of a pale yellow solid which was pureracemic2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide.

Example 10f Preparation of(2s)-2-methyl-2-[[2-(1H-pyrrolo[5,4-b]pyridine-3-yl]amino]-N-(2,2,2-trifluoroethyl)butanamide

The racemic mixture of2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamidefrom the previous step was separated into the two component enantiomersusing SFC chromatography to give as the pure enantiomer, VRT-1071001-1;(2s)-2-methyl-2-[[2-(1H-pyrrolo[5,4-b]pyridine-3-yl]amino]-N-(2,2,2-trifluoroethyl)butanamide.186.7 mg (16.7%). ¹H NMR (300 MHz, MeOD) δ 8.82 (dd, J=8.0, 1.3 Hz, 1H),8.22 (dd, J=4.7, 1.3 Hz, 1H), 8.19-8.04 (m, 2H), 7.22 (dd, J=8.0, 4.8Hz, 1H), 6.42 (d, J=5.9 Hz, 1H), 3.98-3.59 (m, 2H), 3.38-3.24 (m, 3H),2.22 (dq, J=15.0, 7.5 Hz, 1H), 2.03-1.80 (m, 1H), 1.62 (s, 3H),1.01-0.82 (m, 3H). m/e m+1=393.36

Other Embodiments

All publications and patents referred to in this disclosure areincorporated herein by reference to the same extent as if eachindividual publication or patent application were specifically andindividually indicated to be incorporated by reference. Should themeaning of the terms in any of the patents or publications incorporatedby reference conflict with the meaning of the terms used in thisdisclosure, the meaning of the terms in this disclosure are intended tobe controlling. Furthermore, the foregoing discussion discloses anddescribes merely exemplary embodiments of the present invention. Oneskilled in the art will readily recognize from such discussion and fromthe accompanying drawings and claims, that various changes,modifications and variations can be made therein without departing fromthe spirit and scope of the invention as defined in the followingclaims.

1-36. (canceled)
 37. A process for preparing a compound of Formula 4:

wherein: R¹ is —H, —Cl or —F; R² is —H or —F; R³ is —C₁₋₄ aliphaticoptionally substituted with 1-5 occurrences of R⁵; R⁴ is —C₁₋₂ alkyloptionally substituted with 1-3 occurrences of R⁵; or R³ and R⁴ aretaken together to form a 3-7 membered carbocyclic or heterocyclicsaturated ring optionally substituted with 1-5 occurrences of R⁵; eachR⁵ is independently selected from halogen, —OCH₃, —OH, —NO₂, —NH₂, —SH,—SCH₃, —NHCH₃, —CN, or unsubstituted —C₁₋₂ aliphatic, or two R⁵ groups,together with the carbon to which they are attached, form a cyclopropylring; comprising the step of: ia) reacting a compound of Formula 1 witha hydrochloride salt of a compound Formula 2,

in the presence of water, an organic solvent, a base, and a palladiumcatalyst selected from

or any combination thereof, to generate a compound of Formula 3, and

ii) deprotecting the compound of Formula 3 to generate the compound ofFormula
 4. 38. The process of claim 37, wherein the organic solvent ofstep ia) is an alcohol.
 39. The process of claim 38, wherein the alcoholis selected from methanol, ethanol, propanol, isopropanol, butanol,tert-butanol, or any combination thereof.
 40. The process of claim 37,wherein the base of step ia) is an inorganic base.
 41. The process ofclaim 40, wherein the inorganic base is an alkali metal hydroxide. 42.The process of claim 41, wherein the alkali metal hydroxide is NaOH,KOH, or any combination thereof.
 43. The process of claim 37, whereinthe reaction of step ia) is performed at a temperature between about 50°C. and about 110° C.
 44. The process of claim 43, wherein the reactionof step ia) is performed at a temperature between about 60° C. and about95° C.
 45. The process of claim 44, wherein the reaction of step ia) isperformed at a temperature between about 70° C. and about 80° C.
 46. Theprocess of claim 37, wherein the deprotection of step ii) is performedin the presence of a base.
 47. The process of claim 46, wherein the baseis an inorganic base.
 48. The process of claim 47, wherein the inorganicbase is an alkali metal hydroxide.
 49. The process of claim 48, whereinthe alkali metal hydroxide is KOH, NaOH, or any combination thereof. 50.The process of claim 37, further comprising the steps: viiib) reacting acompound of Formula 11 with an acid salt of a compound of Formula 15 inthe presence of a solvent and a base to generate the compound Formula 2:

and ixb) reacting the compound of Formula 2 with HCl to generate thehydrochloride salt of the compound of Formula 2,


51. The process of claim 50, wherein the base of step viiib) is aninorganic base selected from tripotassium phosphate, dipotassiumhydrogen phosphate, dipotassium carbonate, disodium carbonate, trisodiumphosphate, disodium hydrogen phosphate, or any combination thereof. 52.The process of claim 50, wherein the solvent of step viiib) compriseswater.
 53. The process of claim 52, wherein the solvent of step viiib)further comprises an alcohol selected from methanol, ethanol, propanol,iso-propanol, butanol, tert-butanol, or any combination thereof.
 54. Theprocess of claim 50, wherein the reaction of step viiib) is performed ata temperature of from about 70° C. to about 120° C.
 55. The process ofclaim 54, wherein the reaction of step viiib) is performed at atemperature of from about 80° C. to about 100° C. 56-111. (canceled)